Exatecan-derived topoisomerase-1 inhibitor pharmaceutical compositions and uses thereof

Abstract

The present disclosure is directed to alcohol- and amine-containing exatecan derivatives, including those having a structure according to formula (I), where X is as defined in the present disclosure, and pharma- ceutically acceptable salts or solvates thereof. The present disclosure is further directed to pharmaceutical compositions comprising these compounds, and to the use of these compounds and compositions in the prevention or treatment of cancer and / or tumors. [Formula 1] TIFF2025511436000081.tif52145

Description

[Technical field]

[0001] The present disclosure relates to topoisomerase-1 inhibitors derived from the exatecan scaffold that can be used in oncological treatment. [Background technology]

[0002] Topoisomerase-1 inhibitors are cytotoxic chemotherapy drug derivatives that have a camptothecin core. Documents reporting the use of the camptothecin derivative exatecan (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4,:6,7]imidazo[l,2-b]quinoline-10,13(9H,15H)-dione) are disclosed in WO2014057687, US11103593, US9808537, US7091186, US2010 / 0062008, WO2015057699, Clinical Cancer Research (2016) 22(20):5097-5108 and Cancer Sci (2016) 107:1039-1046. See also WO2022068878, WO2017062271, CN113816969, CN112125915 and US20210353764. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] WO2014057687 [Patent Document 2] US11103593 [Patent Document 3] US9808537 [Patent Document 4] US7091186 [Patent Document 5] US2010 / 0062008 [Patent Document 6] WO2015057699 [Patent Document 7] WO2022068878 [Patent Document 8] WO2017062271 [Patent Document 9] CN113816969 [Patent Document 10] CN112125915 [Patent Document 11] US20210353764 [Non-patent literature]

[0004] [Non-Patent Document 1] Clinical Cancer Research (2016) 22(20):5097-5108 [Non-Patent Document 2] Cancer Sci (2016) 107:1039–1046 Summary of the Invention [Problem to be solved by the invention]

[0005] The compounds of the present disclosure represent a class of topoisomerase-1 inhibitors derived from the exatecan scaffold. Specifically, the compounds are described as alcohol- and amine-containing exatecan amides and their analogs. The compounds are cytotoxic and can be used as chemotherapeutic agents in oncological settings, for example as antitumor agents. These compounds are potent, have novel structures, and show activity across multiple cancer cell lines. [Means for solving the problem]

[0006] For each of the following embodiments, any variable not expressly defined in that embodiment is as defined in formula (I). In each embodiment described herein, each variable is selected independently of the others, unless otherwise indicated.

[0007] In one embodiment, the present disclosure provides a compound of formula I: [ka] [During the ceremony, R k is hydrogen, -C 1-6 Alkyl, (CH2) n C(O)NHC 1-6 Alkyl, (CH2) n C 6-10 Aryl and [ka] wherein the alkyl and aryl are selected from hydroxyl, -C 1-6 may be substituted with 1 to 3 alkylOH groups, and the alkyl may be substituted with 1 to 10 halogen groups; R j is hydrogen or C 1-6 alkyl, wherein the alkyl is optionally substituted with 1 to 10 halogens; R 2 and R 3 are independently hydrogen, -C 1-6 Alkyl, OH, -C 1-6 AlkylOH, halogen, -C 1-9 Haloalkyl, -(CH2) n NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 3-6 Cycloalkyl, -(CH2) n C 6-10 Aryl and -(CH2) n O.C. 1-6 alkyl, where R 2 and R 3 cannot both be halogens at the same time; R 4 is C 1-6 Alkyl, OH, -C 1-6 AlkylOH, -CH(OH)C 1-6 Alkyl, -C 1-9 Haloalkyl, halogen, -C 3-6 Cycloalkyl, -(CH2)n O.C. 1-3 Alkyl, -(CH2) n O.C. 1-9 Haloalkyl, -CR x R y C 1-6 AlkylOH, -(CH2) n NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NHC(O)C 1-6 alkylNH2; R x and R y is C 1-3 Represents an alkylene, which, when combined, is C 3-6 Forms a cycloalkyl or spirocycloalkyl; Each n independently represents 0, 1, 2, or 3. The present invention provides alcohol- and amine-containing exatecan derivatives, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, comprising the structure:

[0008] One embodiment of the present disclosure is j is hydrogen.

[0009] Another embodiment of the present disclosure is R j C 1-6 A subembodiment of this aspect of the invention is realized when R is alkyl, which is optionally substituted with 1 to 5 groups of halogen. j C is substituted with 1 to 4 halogens 1-6 This is realized when the aryl group is alkyl.

[0010] One embodiment of the present disclosure is k is hydrogen.

[0011] Another embodiment of the present disclosure is R k Ga-C 1-6 alkyl, the alkyl being 1 to 10 halogens, or hydroxyl and -C 1-6 This is realized when the alkyl group is optionally substituted with 1 to 3 groups selected from alkylOH.

[0012] Another embodiment of the present disclosure is R k But (CH2) n C(O)NHC 1-6 alkyl, the alkyl being 1 to 10 halogens, or hydroxyl and -C 1-6 This is realized when the alkyl group is optionally substituted with 1 to 3 groups selected from alkylOH.

[0013] Another embodiment of the present disclosure is R k (CH2) n C 6-10 aryl, wherein the aryl is hydroxyl and -C 1-6 This is realized when the alkyl group is optionally substituted with 1 to 3 groups selected from alkylOH.

[0014] Another embodiment of the present disclosure is R k but [ka] [Here, R 2 , R 3 and R 4 are as described herein. This is realized when

[0015] One embodiment of the present invention is a compound having the structural formula: [ka] or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

[0016] One embodiment of the present disclosure is 2 , R 3 and R 4 This is achieved when none of the hydrogen atoms in the alkyl-containing substituents of is deuterated.

[0017] Another embodiment of the present disclosure is R 2 , R 3 and R 4This is achieved when at least one hydrogen atom in the alkyl-containing substituent of is deuterated.

[0018] Another embodiment of the present disclosure is realized when n is 0. Another embodiment of the present disclosure is realized when n is 1. Another embodiment of the present disclosure is realized when n is 2. Yet another embodiment of the present disclosure is realized when n is 3.

[0019] Another embodiment of the present disclosure is R x and R y are realized when they combine with the atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0020] Another embodiment of the present disclosure is R 2 But hydrogen, C 1-6 Alkyl, CH2OC 1-6 Alkyl, -(CH2) n OH, -CH2F, -CHF2, -CF3, -(CH2)phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) n A subembodiment of this aspect of the disclosure is realized when R 2 But hydrogen, C 1-6 Another subembodiment of this aspect of the disclosure is realized when R 2 is hydrogen. Another subembodiment of this aspect of the disclosure is 2 is selected from -CH3, -CH2CH3 and -CH2CH(CH3)2 1-6 Another subembodiment of this aspect of the disclosure is realized when R 2 (CH2) n OCH3. Another subembodiment of this aspect of the disclosure is achieved when R 2 is -OH or -CHOH. Another subembodiment of this aspect of the disclosure is2 is -CH2F, -CHF2, or -CF3. Yet another subembodiment of this aspect of the disclosure is realized when R 2 is realized when R 2 This is realized when none of the hydrogen atoms in the alkyl-containing substituents of is deuterated.

[0021] Another embodiment of the present disclosure is R 3 But hydrogen, C 1-6 Alkyl, CH2OC 1-6 Alkyl, -(CH2) n OH, -CH2F, -CHF2, -CF3, -(CH2)phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2) n A subembodiment of this aspect of the disclosure is realized when R 3 But hydrogen, C 1-6 Another subembodiment of this aspect of the disclosure is realized when R 3 is hydrogen. Another subembodiment of this aspect of the disclosure is 3 is selected from -CH3, -CH2CH3 and -CH2CH(CH3)2 1-6 Another subembodiment of this aspect of the disclosure is realized when R 3 is -CH2OCH3. Another subembodiment of this aspect of the disclosure is 3 is -OH or -CHOH. Another subembodiment of this aspect of the disclosure is 3 is -CH2F, -CHF2, or -CF3. Yet another subembodiment of this aspect of the disclosure is realized when R 3 is realized when R 3 This is realized when none of the hydrogen atoms in the alkyl-containing substituents of is deuterated.

[0022] Another embodiment of the present disclosure is R 2 and R 3 This is realized when both are hydrogen.

[0023] Yet another embodiment of the present disclosure is a compound comprising R 2 and R 3 At least one of the groups is -OH or -(CH2) n OH, where n is not 0. One aspect of the present disclosure is 2 and R 3 One of the groups is -OH or -(CH2) n OH, where n is not 0. Another aspect of the present disclosure is 2 and R 3 Yet another aspect of the present disclosure is realized when one of R 2 and R 3 One of them is -OH and the other is hydrogen and C 1-6 Yet another aspect of the present disclosure is realized when R 2 and R 3 is -CHOH and the other is not -CHOH. 2 and R 3 One of them is -CHOH, and the other is hydrogen and C 1-6 Yet another aspect of the present disclosure is realized when R 2 and R 3 One or the other is C 1-6 This is realized when the alkyl group contains an alkyl and the hydrogen in the alkyl group is not deuterated.

[0024] Another embodiment of the present disclosure is R 2 and R 3 At least one of the groups is -(CH2) n This is realized when R is -NH, -NHCH, or -N(CH). One aspect of this embodiment of the present disclosure is 2 and R 3 At least one of them is (CH2) nYet another embodiment is realized when R 2 and R 3 is NH2 and the other is not NH2. Yet another aspect of the present disclosure is 2 and R 3 One of them is NH2, the other is hydrogen, CH2 phenyl and C 1-6 Another embodiment is realized when R 2 and R 3 is CH2NH2 and the other is not CH2NH2. 2 and R 3 One of them is CH2NH2, and the other is hydrogen, CH2phenyl and C 1-6 Yet another aspect of the present disclosure is realized when R 2 and R 3 One or the other is C 1-6 This is realized when the alkyl group contains an alkyl and none of the hydrogens in the alkyl group are deuterated.

[0025] Another embodiment of the present disclosure is R 4 But, C 1-6 Alkyl, -C 1-6 AlkylOH, OH, -CH(OH)C 1-6 Alkyl, -(CH2) n O.C. 1-3 Alkyl, -C 3-6 Cycloalkyl, -C 1-9 Haloalkyl, -(CH2) n O.C. 1-9 Haloalkyl, halogen, -CR x R y C 1-6 AlkylOH, -(CH2) n NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NHC(O)C 1-6 One aspect of this embodiment of the present disclosure is that R 4 But, C 1-6 Alkyl, -(CH2) nOH, -CH(CH3)OH, -CH2F, -CHF2, -CF3, Fluorine, (CH2) n OCHF2, cyclopropyl, -(CH2) n Another aspect of the present disclosure is realized when R 4 But CH3, -(CH2) n Another embodiment of this aspect of the disclosure is realized when R 4 Another embodiment of this aspect of the disclosure is realized when R 4 Ga-(CH2) n Another embodiment of this aspect of the disclosure is achieved when R 4 is -(CH2)2OH or -CH2OH. Another embodiment of this aspect of the disclosure is 4 is -(CH2)2OH. Another embodiment of this aspect of the disclosure is 4 Another embodiment of this aspect of the disclosure is realized when R 4 is -CH(CH3)OH. Another embodiment of this aspect of the disclosure is 4 is -CH2F, -CHF2, or -CF3. Another embodiment of this aspect of the disclosure is 4 Ga-(CH2) n Another embodiment of this aspect of the disclosure is achieved when R 4 is NH2. Another embodiment of this aspect of the disclosure is 4 is NHC(O)CH(CH3)NH2. Another embodiment of this aspect of the disclosure is 4 But -CR x R y C 1-6 AlkylOH (where R x and R y is an alkylene substituent, which alkylenes combine to form cyclopropyl or spirocyclopropyl. Another embodiment of this aspect of the disclosure is 4is -spirocyclopropylCHOH. Another embodiment of this aspect of the disclosure is 4 Ga-(CH2) n OCHF2 or CHF2. Yet another aspect of the present disclosure is 4 C 1-6 This is realized when the alkyl group contains an alkyl and none of the hydrogens in the alkyl group are deuterated.

[0026] Another embodiment of the present disclosure is R 2 and R 3 One of the groups is -OH or -(CH2) n OH (where n is not 0) and R 4 is C 1-6 Alkyl, -C 1-6 AlkylOH, -(CH2) n O.C. 1-3 Alkyl, -CH(OH)C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-9 Haloalkyl, -(CH2) n O.C. 1-9 Haloalkyl, halogen, -CR x R y C 1-6 AlkylOH, -(CH2) n NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NHC(O)C 1-6 Yet another aspect of the present disclosure is when R 2 and R 3 One of the groups is -OH or -CHOH, and the other is hydrogen and C 1-6 alkyl; R 4 is CH3, -(CH2) n OH, -CH(CH3)OH, -CH2F, -CHF2, -CF3, Fluorine, (CH2) n OCHF2, cyclopropyl, -(CH2) n This is realized when R is selected from -NH and -spirocyclopropylCHOH, -NHC(O)CH(CH)NH. One embodiment of this aspect of the disclosure is 2and R 3 One of the groups is -OH or -(CH2) n OH (where n is not 0), and the other is hydrogen and C 1-6 alkyl; R 4 are CH3, -(CH2)2OH, -CH2OH, -CH(CH3)OH, -CH2F, -CHF2, -CF3, fluorine and -(CH2) n Another embodiment of this aspect of the disclosure is achieved when R 2 and R 3 One of the groups is -OH or -(CH2) n OH (where n is not 0), and the other is hydrogen and C 1-6 alkyl; R 4 are CH3, -(CH2)2OH, -CH2OH and -(CH2) n An aspect of the present disclosure is realized when n is 0, 1, or 2. Yet another aspect of the present disclosure is realized when R 2 , R 3 and / or R 4 C 1-6 This is realized when the alkyl group contains an alkyl and none of the hydrogens in the alkyl group are deuterated.

[0027] Another embodiment of the present disclosure is R 2 and R 3 One of them is -(CH2) n NH2, -NHCH3 or -N(CH3)2, and the other is hydrogen, CH2 phenyl and C 1-6 alkyl; R 4 is C 1-6 Alkyl, -C 1-6 AlkylOH, -CH(OH)C 1-6 Alkyl, -(CH2) n O.C. 1-3 Alkyl, -C 3-6 Cycloalkyl, -C 1-9 Haloalkyl, -(CH2) n O.C. 1-9 Haloalkyl, halogen, -CR x R y C 1-6 AlkylOH, -(CH2)n NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NHC(O)C 1-6 Yet another aspect of the present disclosure is when R 2 and R 3 One of them is (CH2) n NH2, -NHCH3 or -N(CH3)2, and the other is hydrogen, CH2 phenyl and C 1-6 alkyl; R 4 is CH3, -(CH2) n OH, -CH(CH3)OH, -CH2F, -CHF2, -CF3, Fluorine, (CH2) n OCHF2, cyclopropyl, -(CH2) n NH2, and -spirocyclopropylCH2OH, -NHC(O)CH(CH3)NH2. One embodiment of this aspect of the disclosure is 2 and R 3 One of them is (CH2) n NH2, -NHCH3 or -N(CH3)2, and the other is hydrogen, CH2 phenyl and C 1-6 alkyl; R 4 is CH3, -(CH2) n OH, -CH(CH3)OH, -CH2F, -CHF2, -CF3, fluorine and -(CH2) n Another embodiment of this aspect of the disclosure is achieved when R 2 and R 3 One of them is (CH2) n NH2, -NHCH3 or -N(CH3)2, and the other is hydrogen, CH2 phenyl and C 1-6 alkyl; R 4 is -(CH2) n OH or -(CH2) n One aspect of the present disclosure is achieved when R 4 Another aspect of the present disclosure is realized when R 4 Another aspect of the present disclosure is realized when R 4 (CH2)n Yet another aspect of the present disclosure is when R 2 , R 3 and / or R 4 C 1-6 This is realized when the alkyl group contains an alkyl and none of the hydrogens in the alkyl group are deuterated.

[0028] Another embodiment of the present disclosure is R 2 and R 3 are hydrogen and R 4 is CH3, -(CH2) n OH, -CH(CH3)OH, -CH2F, -CHF2, -CF3, Fluorine, (CH2) n OCHF2, cyclopropyl, -(CH2) n This is realized when the alkyl group is selected from -NH2 and -spirocyclopropylCH2OH, -NHC(O)CH(CH3)NH2.

[0029] Another embodiment of the disclosure of Formula I and Formula I' is represented by structural formula II: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 4 is as described herein. Subembodiments of the disclosure of Formula II include 4 -CH3, -OH, -CH2OH, -(CH2)2OH, -CH(CH3)OH, (CH2)2OCHF2, -C(CH3)2CH2OH, -CH2F, -CHF2, -CF3, fluorine and -(CH2) n A subembodiment of the disclosure of formula II is realized when R 4 A subembodiment of the disclosure of formula II is realized when R 4 A subembodiment of the disclosure of formula II is realized when R 4 A subembodiment of the disclosure of formula II is realized when R 4 Another subembodiment of the disclosure of formula II is realized when R4 Another subembodiment of the disclosure of formula II is realized when R 4 Another subembodiment of the disclosure of formula II is realized when R 4 is -CH2F, -CHF2, or -CF3. A subembodiment of the disclosure of formula II is realized when R 4 A subembodiment of the disclosure of formula II is realized when R 4 Ga-(CH2) n Another subembodiment of the disclosure of formula II is realized when R 4 C 1-6 This is realized when the alkyl group contains an alkyl and none of the hydrogens in the alkyl group are deuterated.

[0030] Another embodiment of the disclosure of Formula I and Formula I' is represented by structural formula III: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 4 is as described herein. Subembodiments of the disclosure of formula III include 4 CH3, -CH2OH, -(CH2)2OH, -CH(CH3)OH, (CH2)2OCHF2, -C(CH3)2CH2OH, halogens, -CH2F, -CHF2, -OH, -CF3 and -(CH2) n A subembodiment of the disclosure of formula III is realized when R 4 A subembodiment of the disclosure of formula II is realized when R 4 A subembodiment of the disclosure of formula III is realized when R 4 A subembodiment of the disclosure of formula III is realized when R 4 Another subembodiment of the disclosure of formula III is realized when R 4 Another subembodiment of the disclosure of formula III is realized when R4 Another subembodiment of the disclosure of formula III is realized when R 4 Another subembodiment of the disclosure of formula III is realized when R 4 is fluorine. A subembodiment of the disclosure of formula III is realized when R 4 Ga-(CH2) n Another subembodiment of the disclosure of formula III is realized when R 4 C 1-6 This is realized when the alkyl group contains an alkyl and none of the hydrogens in the alkyl group are deuterated.

[0031] Another embodiment of the disclosure of Formula I and Formula I' is represented by structural formula IV: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 4 is as described herein. Subembodiments of the disclosure of formula IV include 4 is OH, -CH2F, -CHF2, -CF3, fluorine or (CH2) n This is realized when the compound is NH2.

[0032] Another embodiment of the disclosure of Formula I and Formula I′ is represented by structural formula V: [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R j is as described herein. Subembodiments of the disclosure of Formula V include j C 1-6 This is realized when the alkyl is optionally substituted with 1 to 10 halogen groups.

[0033] Another embodiment of formula V is where R is hydrogen or -C 1-6 This is realized when the aryl group is alkyl.

[0034] Another embodiment of formula V is R k1 Ga-C 1-6 alkyl, the alkyl being 1 to 10 halogens and / or hydroxyl and -C 1-6 A subembodiment of this aspect of the invention is realized when R k1 Ga-C 1-6 alkyl, the alkyl being selected from hydroxyl and -C 1-6 This is realized when the alkyl group is substituted with 1 to 3 groups selected from alkylOH and / or with 1 to 10 halogens.

[0035] Another embodiment of the present disclosure is R k1 (CH2) n C(O)NHC 1-6 alkyl, the alkyl being 1 to 10 halogens and / or hydroxyl and -C 1-6 This is realized when the alkyl group is optionally substituted with 1 to 3 groups selected from alkylOH.

[0036] Another embodiment of the present disclosure is R k1 (CH2) n C 6-10 aryl, wherein the aryl is hydroxyl and -C 1-6 This is realized when the alkyl group is optionally substituted with 1 to 3 groups selected from alkylOH.

[0037] One aspect of the present disclosure relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I, Formula I', Formula II, Formula III, Formula IV, Formula V, or a pharma- ceutically acceptable salt or solvate thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0038] Another aspect of the present disclosure relates to a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula I, Formula I', Formula II, Formula III, Formula IV or Formula V as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer or mixture thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents or excipients.

[0039] Another aspect of the present disclosure relates to a compound of formula I, I', II, III, IV or V as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer or mixture thereof, or a pharma- ceutically acceptable salt thereof, for use as a medicament or pharmaceutical ingredient.

[0040] Another aspect of the present disclosure relates to a compound of formula I, I', II, III, IV or V as described herein or a tautomer, mesomere, racemate, enantiomer, diastereomer or mixture thereof or a pharma- ceutically acceptable salt or pharmaceutical composition thereof in the preparation of a medicament for treating or preventing a tumor.

[0041] In another embodiment, the compounds of the present disclosure include those compounds identified herein as examples in the table below, and pharma- ceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may exist depending on the nature of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and it is intended that all possible optical isomers and diastereomers, in mixtures and as pure or partially purified compounds, are included within the scope of the present disclosure. Unless a specific stereochemistry is indicated, the present disclosure is intended to encompass all such isomeric forms of these compounds.

[0043] The independent syntheses of these diastereomers or their chromatographic separations may be carried out as known in the art using appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be confirmed, inter alia, by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

[0044] If desired, racemic mixtures of compounds can be separated so that the individual enantiomers are isolated. This separation can be carried out by methods well known in the art, for example by coupling a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods such as fractional crystallization or chromatography. The coupling reaction often involves the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to the pure enantiomer by cleavage of the added chiral residue. Racemic mixtures of compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which are well known in the art.

[0045] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0046] In the compounds of formula I, formula I', formula II, formula III, formula IV or formula V, the atoms may exhibit natural isotopic abundance or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure may encompass all suitable isotopic variations of the compounds of general formula I, general formula I', general formula II, general formula III, general formula IV or general formula V. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced required dosage) or provide compounds useful as standards for characterization of biological samples. For purposes of the present invention, when a compound is said to be "non-deuterated," it means that it is not enriched in deuterium above background conditions. Isotopically enriched compounds within the scope of formula I, formula I', formula II, formula III, formula IV, or formula V can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0047] When the compounds of the present disclosure can form tautomers, all such tautomeric forms are also included within the scope of the present disclosure. For example, compounds containing a carbonyl -CH2C(O)- group (keto form) can undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). When both keto and enol forms exist, they are both included within the scope of the present disclosure.

[0048] Any variable part (e.g., R 5 When any of the following occurs more than once in any constituent, its definition at each occurrence is independent at every other occurrence. Additionally, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn from substituents into ring systems represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.

[0049] It is understood that one skilled in the art can incorporate one or more silicon (Si) atoms into the compounds of the present disclosure in place of one or more carbon atoms to provide compounds that are chemically stable and can be easily synthesized from readily available starting materials by techniques known to those skilled in the art. Carbon and silicon have different covalent bond radii, which results in differences in bond distances and configurations when comparing bonds between similar C and Si elements. These differences result in subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One skilled in the art will understand that size and shape differences can result in subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, etc. (Diass, JO et al. Organometallics (2006) 5:1188-1198; Showell, GA et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

[0050] It is understood that those skilled in the art can select the substituents and substitution patterns in the compounds of the present disclosure to provide chemically stable compounds that can be easily synthesized from readily available starting materials by techniques known in the art and the methods described below.It is understood that when a substituent itself is substituted with two or more groups, these multiple groups can be present on the same carbon or on different carbons, as long as a stable structure is obtained.The expression "optionally substituted with one or more substituents" should be understood to mean that the group can be unsubstituted or substituted with one or more substituents.

[0051] The absolute stereochemistry is illustrated using hashed and solid wedge bonds, as shown in Illus-I and Illus-II. Thus, the methyl group in Illus-I emerges from the plane of the paper, and the ethyl group in Illus-II descends into the plane of the paper with the cyclohexene ring in the plane of the paper. The hydrogen on the same carbon as the methyl group in Illus-I descends into the plane of the paper, and the hydrogen on the same carbon as the ethyl group in Illus-II is presumed to emerge from the plane of the paper. The rule is similar when both a hashed rectangle and a solid rectangle are attached to the same carbon, as shown in Illus-III, with the methyl group emerging from the plane of the paper and the ethyl group descending into the plane of the paper with the cyclohexene ring in the plane of the paper. [ka]

[0052] As is conventional, unless otherwise indicated in the accompanying text, a regular "rod" or "wavy" bond indicates that all possible stereochemistries are represented, including pure compounds, mixtures of isomers, and racemic mixtures.

[0053] As used herein, the following terms have the following meanings unless otherwise indicated.

[0054] The phrase "at least one" used in reference to the number of components that make up a composition, e.g., "at least one pharmaceutical excipient," means that one member of the specified group is present in the composition, and that more than one member may additionally be present. A component of a composition is typically an aliquot of an isolated pure substance that is added to the composition, where the purity level of the isolated substance added to the composition is the normally accepted purity level for that type of reagent.

[0055] The phrase "one or more" has the same meaning as "at least one" whether used in reference to a substituent on a compound or a component of a pharmaceutical composition.

[0056] An "effective amount" or a "therapeutically effective amount" is intended to describe providing an amount of at least one compound of the present disclosure or an amount of a composition comprising at least one compound of the present disclosure that is effective in treating or suppressing a disease or condition described herein, thus resulting in a desired therapeutic, ameliorative, suppressive or preventive effect. For example, in the treatment of a disease or disorder of the central nervous system with one or more of the compounds described herein, an "effective amount" (or a "therapeutically effective amount") means providing at least one compound of Formula I, Formula I', Formula II, Formula III, Formula IV or Formula V in an amount that results in a therapeutic response in a patient suffering from a disease or disorder of the central nervous system ("condition"), which includes a response suitable for managing, alleviating, improving or treating the condition, or alleviating, improving, reducing or eradicating the condition and / or one or more symptoms responsible for the long-term stabilization of the condition, which may be ascertained, for example, by analysis of pharmacodynamic markers or clinical evaluation of the patient suffering from the condition.

[0057] "Patient" and "subject" mean animals, such as mammals (eg, humans), and preferably humans.

[0058] "Prodrug" refers to a compound that is rapidly converted to the parent compound in vivo, for example by hydrolysis in blood (e.g., conversion of a prodrug of Formula I-V to a compound represented by Formula I, Formula I', Formula II, Formula III, Formula IV or Formula V or a salt thereof); a full discussion can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference). The scope of the present disclosure includes prodrugs of the novel compounds of the present disclosure.

[0059] The term "substituted" means that one or more of the recited substituents can occupy one or more of the bonding positions on the substrate typically occupied by "-H", provided that such substitution does not exceed the normal valence rules of the atoms in the bonding configuration present in the substrate, and provided that such substitution ultimately results in stable compounds, i.e., such substitutions do not result in compounds having mutually reactive substituents located geminal or vicinal to one another; and where such substitutions provide compounds that are sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

[0060] When optional substitution of a moiety is described (e.g., "optionally substituted"), this term means that, when substituents are present, one or more of the recited substituents for a specified substrate can be present on the substrate at a bonding position normally occupied by the default substituent normally occupying that position. For example, the default substituent on a carbon atom of an alkyl moiety is a hydrogen atom, and an optional substituent can replace that default substituent.

[0061] As used herein, unless otherwise indicated, the following terms used to describe moieties have the following meanings, whether including the entire definition of a variable of a structural representation of a compound of the disclosure or including the substituents attached to a variable of a structural representation of a group of a compound of the disclosure, and, unless otherwise indicated, the definition of each term (i.e., moiety or substituent) applies when the term is used individually or as a component of another term (e.g., the definition of aryl is the same for aryl and for aryl moieties such as arylalkyl, alkylaryl, and arylalkynyl moieties); moieties are equivalently described herein by structural, typographical, or chemical terms without any intended distinction in meaning. For example, an "acyl" substituent is referred to herein by the term "acyl," by the typographical representation "R'-(C=O)-" or "R'-C(O)-," or by the structural representation [ka] and using some or all of these expressions is equivalent without distinction.

[0062] The term "alkyl" (which includes the alkyl portions of other moieties such as trifluoromethyl-alkyl- and alkoxy-) means a straight- or branched-chain aliphatic hydrocarbon moiety containing up to about 20 carbon atoms (e.g., the designation "C 1-20("C-alkyl" refers to an aliphatic hydrocarbon moiety having 1 to 20 carbon atoms.) In some embodiments, alkyl preferably contains up to about 10 carbon atoms, unless the term is modified by an indication that a shorter chain is contemplated; for example, alkyl moieties of 1 to 8 carbon atoms are referred to herein as "C 1-8 When the term "alkyl" is indicated with two hyphens (i.e., "-alkyl-"), it indicates that the alkyl moieties are attached in such a way that they link the substituents on either side of them. For example, "-alkyl-OH" indicates an alkyl moiety that links a hydroxyl moiety to a substrate.

[0063] The term "cycloalkyl" refers to a moiety having a main hydrocarbon chain forming a monocyclic or bicyclic cycloaliphatic moiety containing at least 3 carbon atoms (the minimum number necessary to provide a monocyclic moiety) up to the specified maximum number of carbon atoms (generally 8 for monocyclic moieties and 10 for bicyclic moieties, including spirocyclic moieties). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The term "cycloalkyl" also generally encompasses non-aromatic fused polycyclic ring systems containing up to 20 carbon atoms, which may be substituted as defined herein for "alkyl". Suitable polycyclic cycloalkyls include, but are not limited to, the following: 1-decalin; norbornyl; adamantyl, and the like.

[0064] As used herein, the term "alkylene" refers to a straight or branched chain saturated aliphatic hydrocarbon group having two residues derived from removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. Alkylene is a straight or branched chain group having 1 to 20 carbon atoms (preferably, 1 to 12 carbon atoms, more preferably, 1 to 6 carbon atoms). Non-limiting examples are methylene, ethylene, propylene, butylene, pentylene, etc.

[0065] As used herein, the term "alkyl" when modified by "substituted" or "optionally substituted" means that one or more C-H bonds in the alkyl moiety are either replaced or optionally substituted by a substituent bonded to the alkyl group referred to in defining the moiety.

[0066] The term "cycloalkyl" denotes a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyls include cycloalkyls having spiro, fused, or bridged rings.

[0067] When a structural formula represents a bond between a moiety and a substrate using a bond line that ends midway through the structure, for example, the following representation: [ka] In the case of a ring structure, whether numbered or not, the structure indicates that the moiety can be attached to the substrate through any of the available ring atoms (e.g., the numbered atoms of the exemplary moieties above), unless otherwise defined.

[0068] The term "aryl" refers to 6-14 membered all carbon monocyclic or fused polycyclic rings (i.e., each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) having a conjugated it-electron system, preferably 6-10 membered aryl, such as phenyl and naphthyl, preferably phenyl.

[0069] The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic ring system, 8-12 membered bicyclic ring system, or 11-14 membered tricyclic ring system having 1-3 heteroatoms in the monocyclic ring, 1-6 heteroatoms in the bicyclic ring, or 1-9 heteroatoms in the tricyclic ring, where the heteroatoms are selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S in the monocyclic, bicyclic, or tricyclic ring, respectively). Non-limiting examples of heteroaryl are pyridyl, pyrazolyl, pyrimidinyl, furanyl, oxazolyl, triazolyl, oxadiazolyl, and thiophenyl. The heteroaryl groups described herein can also include fused rings that share a common carbon-carbon bond.

[0070] The term "heterocyclyl" (or heterocycloalkyl) means a non-aromatic mono- or polycyclic saturated ring system containing 3 to 10 ring atoms (preferably 5 to 10 ring atoms), wherein one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen (e.g., piperidyl- or pyrrolidinyl), oxygen (e.g., furanyl and tetrahydropyranyl), or sulfur (e.g., tetrahydrothiophenyl and tetrahydrothiopyranyl), and wherein the heteroatoms may be alone or in combination, provided that the moiety does not contain adjacent oxygen and / or sulfur atoms present in the ring system; preferred heterocyclyl moieties contain 5 to 6 ring atoms; the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom; the heterocyclyl can be substituted by one or more independently selected substituents.

[0071] The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide (SO2); non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, [ka] (wherein, unless otherwise indicated, the moiety is attached to the substrate through any of the ring carbon atoms C2, C3, C5, or C6), thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like; and polycyclic heterocyclyl compounds, such as those having the structure: [ka] A part having the above.

[0072] The term "solvate" refers to a pharma- ceutically acceptable solvate formed by a compound of the present disclosure with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate, etc.

[0073] The term "halogen" means fluorine, chlorine, bromine or iodine; preferred halogens are fluorine, chlorine and bromine unless otherwise indicated when this term is used, and a substituent that is a halogen atom means -F, -Cl, -Br or -I; "halo" means a fluoro, chloro, bromo or iodo substituent bonded to a defined moiety, for example, "haloalkyl" means an alkyl as defined above where one or more of the bonding positions on the alkyl moiety that are typically occupied by hydrogen atoms are instead occupied by a halo group, and perhaloalkyl (or "fully halogenated" alkyl) means that all bonding positions not involved in bonding the alkyl substituent to a substrate are occupied by halogens, for example, when the alkyl is selected to be methyl, the term perfluoroalkyl means -CF.

[0074] The terms "hydroxyl" and "hydroxy" refer to a HO- group, "hydroxyalkyl" refers to a substituent of the formula: "HO-alkyl-", where the alkyl group is attached to its substrate and may be substituted or unsubstituted as defined above; preferred hydroxyalkyl moieties include lower alkyl; non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl; and bond orders are indicated with hyphens where the moieties are represented literally, e.g., -alkyl indicates a single bond between the substrate and the alkyl moiety, and -alkyl-X indicates that the alkyl group attaches the "X" substituent to the substrate. And, in structural representations, bond orders are indicated with wavy lines terminating the bond representations, e.g., [ka] indicates that the methylphenyl moiety is attached to the substrate through the carbon atom ortho to the methyl substituent, whereas a bond representation drawn in a structure ending in a dashed line and without specifically indicating the atom to which it is attached indicates that the moiety can be attached to the substrate through any of the atoms in that moiety available for attachment as explained in the examples above.

[0075] The line "-", as a bond, generally indicates a mixture or either of the possible isomers (eg, isomers containing (R)- and (S)-stereochemical configurations).

[0076] Additionally, bold non-wedge or hashed non-wedge lines are used in structures containing multiple stereocenters to depict the relative configurations when the relative configurations are known. For example: [ka] The fluorine and hydrogen atoms are on the same face of the piperidine ring, but the possible isomers on the right [ka] or one of their isomers, wherein [ka] is the possible isomer on the right [ka] or one of their isomers.

[0077] In all cases, the compound name accompanies the drawn structure and is intended to capture each of the possible stereochemical variations for a given structural isomer based on the synthetic procedures used in its preparation. The listing of individual stereoisomers is connected using or indicates that the compound presented (e.g., "Example Number") was isolated as a single stereoisomer and that the identity of that stereoisomer corresponds to one of the possible configurations listed. The listing of individual stereoisomers is connected using or indicates that the compound presented was isolated as a racemic or diastereomeric mixture.

[0078] Specific absolute configurations are indicated using a bold wedge or a hashed wedge. Unless a specific absolute configuration is indicated, the present disclosure is intended to encompass all such stereoisomeric forms of these compounds.

[0079] As used herein, when more than one oxygen and / or sulfur atom is present in a ring system, an adjacent oxygen and / or sulfur atom cannot be present in the ring system.

[0080] As is well known in the art, a bond drawn from a particular atom, unless a moiety is drawn at the end of that bond, represents a methyl group attached to that atom through that bond, unless otherwise indicated. For example: [ka] teeth, [ka] Represents.

[0081] Any unsatisfied valence in the text, schemes, examples, structures and tables herein is assumed to have one or more hydrogen atoms sufficient to satisfy the valence.

[0082] One or more compounds of the present disclosure may also exist as a solvate or may be converted to a solvate in some cases. The preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611(2004) describes the preparation of solvates of the fungicide fluconazole in ethyl acetate and from water. Similar preparations of solvates and hemisolvates, including hydrates (where the solvent is water or aqueous), are described by EC van Tonder et al., AAPS PharmSciTech., 5(1), article 12(2004) and AL Bingham et al., Chem. Commun., 603-604(2001). A typical, non-limiting process involves dissolving a compound of the invention in a desired amount of a desired solvent (e.g., an organic solvent, an aqueous solvent, water, or a mixture of two or more thereof) at above ambient temperature and cooling the solution, with or without an antisolvent, at a rate sufficient to form crystals, which are then isolated by standard methods. Analytical techniques (e.g., IR spectroscopy) show the presence of the solvent (including water) in the crystals as a solvate (or hydrate if water is incorporated into the crystalline form).

[0083] The present disclosure also encompasses the compounds of the present disclosure in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of formula I, formula I', formula II, formula III, formula IV or formula V, as well as polymorphic forms of the salts, solvates and prodrugs of the compounds of formula I, formula I', formula II, formula III, formula IV or formula V, are intended to be encompassed by the present disclosure. Certain compounds of the present disclosure may exist in various isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). Compounds of the present invention encompass all isomeric forms thereof, both in pure form and as mixtures of two or more types, including racemic mixtures.

[0084] Similarly, unless otherwise indicated, providing a structural representation of a tautomeric form of a compound that exhibits tautomerism is intended to encompass all such tautomeric forms of the compound. Thus, where the disclosed compounds, their salts, and solvates and prodrugs thereof may exist in different tautomeric forms or in equilibrium between such forms, all such forms of the compounds are encompassed by and within the scope of the disclosure. Examples of such tautomers include, but are not limited to, ketone / enol tautomeric forms, imine-enamine tautomeric forms, and tautomeric forms such as, for example, the moieties: [ka] and heteroaromatic forms such as:

[0085] The expression "pharmacologically acceptable" is used herein to indicate compounds, substances, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0086] As used herein, "pharmaceutically acceptable salts" refers to derivatives in which the parent compound is modified by making its acid or base salts. Salts in solid form can exist in two or more crystal structures and can also exist in the form of hydrates. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali or organic salts of acidic residues (e.g., carboxylic acids); and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids (e.g., formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like) and those prepared from organic acids (e.g., acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like). Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric acid, ferrous acid, lithium, magnesium, manganic acid, manganous, potassium, sodium, zinc, and the like.

[0087] When the compound of the present disclosure is basic, salts can be prepared from pharma- ceutically acceptable non-toxic acids, including inorganic and organic acids.Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.In one embodiment of the present disclosure, the salts are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid and tartaric acid.Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0088] The term "toxic drug" refers to a substance that inhibits or stops the function of a cell and / or causes cell death or destruction. Toxic drugs include toxins and other compounds that can be used in the treatment of tumors.

[0089] The term "toxin" refers to any substance that can have a detrimental effect on cell growth or proliferation. The toxin can be a small molecule toxin and its derivatives derived from bacteria, fungi, plants or animals, such as camptothecin derivatives, e.g., exatecan, maytansinoids and its derivatives (CN101573384), e.g., DM1, DM3, DM4, auristatin F (AF) and its derivatives, e.g., MMAF, MMAE, 3024 (WO2016 / 127790A1, compound 7), diphtheria toxin, exotoxins, ricin A chain, abrin A chain, modeccin, a-sarcin, Aleutites fordii toxic protein, dianthin toxic protein, Phytolaca americana toxic protein, Momordica charantia inhibitor, curtin, crotin, Sapaonaria ojficinalis inhibitor, gelonin, mitogenin, restrictocin, phenomycin, enomycin, and trichothecenes.

[0090] The term "chemotherapeutic agent" refers to a compound that can be used to treat tumors. This definition also includes antihormonal agents, which act to regulate, reduce, block or inhibit the action of hormones that promote the growth of cancer, often in the form of systemic or holistic therapy. They may also be hormones. Examples of chemotherapeutic agents include: alkylating agents, such as thiotepa; cyclophosphamide (CYTOXANTM); alkylsulfonates, such as busulfan, improsulfan and piposulfan; aziridines, such as venadopa, carboquone, metuldopa and uredopa; aziridines and methylamelanamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylamine. melamine; nitrogen mustards, for example, chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, nitrovin hydrochloride; melphalan, nobembicin, phenesterine, prednimustine, trofosfamide, uramustine; nitrosureas, for example, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, for example, aclacinomycin, cin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, calicheamicin, carabicin, chromomycin, carzinophilin, chromomycin, actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxy-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, Potfilomycin, puromycin, keramycin, rodorubicin, streptonigrin; streptozocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate, 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; pterin analogues such as fludarabine, 6-mercaptopterin, thiomethopterin, thioguanopterin;Pyrimidine analogues, such as ancitabine, azacitidine, 6-azuridine, carmofur, cytarabine, dideoxyuridine, doxitluridine, enocitabine, floxuridine, 5-FU; androgens, such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenergics, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diazicon; elfomitine; ethoxylated acetate Liptinium;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Lonidamine;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pintostatin;Phenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;PSK;Razoxane;Sizofiran;Spirogermanium;Tenuazonic acid;Triazicon;2,2',2"-Trichlorotriethylamine;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Dibromodulcitol;Pipobroman;Gacytosine;Arabinoside ("Ara-C");Cyclophosphamide;Thiotepa;Taxanes, e.g., Paclitaxel (TAXOL, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunorubicin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitors RFS2000; difluoromethylomitin (DMFO); retinoic acid esperamicin; capecitabine;and pharmaceutically acceptable salts, acids or derivatives of the above substances. Also included in this definition are antihormonal drugs capable of regulating or inhibiting the action of hormones on tumors, where such antihormonal agents include, for example, antiestrogens such as tamoxifen, raloxifene, aromatase inhibitors 4(5)-imidazole, 4-hydroxytamoxifen, trioxyphene, keoxyphene, LYll 7018, onapristone and fareston; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and pharmaceutically acceptable salts, acids or derivatives of the above substances.;

[0091] The term "treating" or "treatment" as used herein (e.g., the term "treating" or "treatment" of a disease, disorder, or condition or associated symptoms, which may be referred to, together or individually, as an "indication"), includes: inhibiting a disease, disorder, or condition, i.e., inhibiting or reducing the onset of the disease or its biological processes or its progression or clinical symptoms; or alleviating the disease, i.e., causing regression of the disease or its biological processes or progression and / or its clinical symptoms. As used herein, "treatment" further refers to controlling, ameliorating, or reducing the risk to a subject suffering from a disease, disorder, or condition involving a tumor. As used herein, the term "preventing" or "prevention" or "prophylaxis" of a disease, disorder, or condition includes: preventing the onset or progression of clinical symptoms of a disease, disorder, or condition in a mammal that may be exposed to or susceptible to the disease, disorder, or condition, but has not yet experienced or exhibited symptoms of the disease, etc.

[0092] As will be appreciated by those of skill in the art, the subjects treated by the methods described herein are generally mammals, which include humans and non-human animals, such as laboratory animals and companion animals. The term "therapeutically effective amount" refers to that amount of the subject compound that elicits the biological or medical response in a tissue, system, animal or human that is desired by a researcher, veterinarian, physician, or other clinician.

[0093] The term "composition" as used herein is intended to include a product that includes a compound of the present disclosure or a pharma- ceutically acceptable salt thereof together with a specific amount of one or more additional specific ingredients, and a product that results directly or indirectly from the combination of a specific amount of a specific ingredient. In the context of pharmaceutical compositions, the term is intended to include a product that includes an active ingredient (which includes a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, optionally together with one or more additional active ingredients) and an inactive ingredient that constitutes a carrier; and a product that results directly or indirectly from the combination, complexation or assembly of two or more ingredients, from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical composition of the present disclosure includes a composition made by mixing a compound of the present disclosure or a pharma- ceutically acceptable salt thereof with a pharma- ceutical acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0094] As noted above, additional embodiments of the present disclosure are directed to methods of treating a disease, disorder, or condition, or one or more symptoms thereof ("indications"), respectively, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or salt thereof.

[0095] In another embodiment, the disclosure is directed to a method of manufacturing a medicament for use in a subject, the method comprising combining a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, with a pharmaceutical carrier or diluent.

[0096] In one such embodiment, the present invention relates to a method for treating breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and In one embodiment, the present invention provides a method of treating or preventing a cancer selected from the group consisting of lymphomas (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or recurrent anaplastic large cell lymphoma) in a subject in need of such treatment, the method comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure, or a pharmacologic acceptable salt or solvate thereof, or a pharmaceutical composition comprising the compound, salt or solvate thereof. In one such embodiment, the subject is a human.

[0097] Another aspect of the present disclosure relates to a method for treating and / or preventing a tumor, comprising administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present disclosure.

[0098] Combination with additional therapeutic agents is also contemplated in the method of the present invention.For example, the combination of the compounds of the present disclosure with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists is useful in treating certain malignant tumors.PPAR-γ and PPAR-δ are nuclear peroxisome proliferator-activated receptors γ and δ.PPAR-γ agonists have been shown to inhibit angiogenic responses to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice (Arch. Ophthamol. 2001; 119:709-717). Examples of PPAR-gamma agonists and PPAR-gamma / alpha agonists include, but are not limited to, thiazolidinediones (e.g., DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (USSN No. 60 / 244,697), or a pharmaceutically acceptable salt thereof.

[0099] Another embodiment of the present disclosure is the use of the compounds of the present disclosure in combination with gene therapy to treat cancer.For a review of genetic strategies to treat cancer, see Hall et al. (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe et al. (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000).Gene therapy can be used to deliver any tumor suppressor gene. Examples of such genes include, but are not limited to, p53, which can be delivered by recombinant virus-mediated gene transfer (see, e.g., U.S. Patent No. 6,069,134), uPA / uPAR antagonists ("Adenovirus-Mediated Delivery of a uPA / uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice", Gene Therapy, 1998;5(8):1105-13), and interferon gamma (J. Immunol. 2000;164:217-222).

[0100] The compounds of the present disclosure may also be administered in combination with inhibitors of inherent multidrug resistance (MDR), particularly in combination with inhibitors of MDR associated with high levels of expression of transporter proteins, such as inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853, and PSC833 (valspodar) or pharma- ceutical acceptable salts thereof.

[0101] The compounds of the present disclosure may also be administered together with immune enhancing agents (eg, levamisole, isoprinosine and Zadaxin or pharma- ceutically acceptable salts thereof).

[0102] The compounds of the present disclosure may also be useful in treating or preventing cancer in combination with P450 inhibitors, including xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, metyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone, and nelfinavir, or a pharma- ceutically acceptable salt thereof.

[0103] Compounds of the present disclosure may also be useful in treating or preventing cancer in combination with Pgp and / or BCRP inhibitors, including cyclosporine A, PSC833, GF120918, cremophor EL, fumitremorgin C, Ko132, Ko134, Iressa, imatinib mesylate, EKI-785, Cl1033, novobiocin, diethylstilbestrol, tamoxifen, resperpin, VX-710, tryprostatin A, flavonoids, and the like. id, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin, and talinolol, or a pharma- ceutically acceptable salt thereof.

[0104] The compounds of the present disclosure may also be useful in treating or preventing cancer, including bone cancer, in combination with bisphosphonates, including, but not limited to, etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate, and tiludronate, including any and all pharma- ceutically acceptable salts, derivatives, hydrates, and mixtures thereof.

[0105] The compounds of the present disclosure may also be useful in treating or preventing breast cancer in combination with aromatase inhibitors, including but not limited to anastrozole, letrozole, and exemestane, or a pharma- ceutically acceptable salt thereof.

[0106] The compounds of the present disclosure may also be useful in treating or preventing cancer in combination with siRNA therapeutics.

[0107] The compounds of the present disclosure may also be administered in combination with gamma-secretase inhibitors and / or inhibitors of NOTCH signaling, including those compounds or pharma- ceutically acceptable salts thereof described in WO01 / 90084, WO02 / 30912, WO01 / 70677, WO03 / 013506, WO02 / 36555, WO03 / 093252, WO03 / 093264, WO03 / 093251, WO03 / 093253, WO2004 / 039800, WO2004 / 039370, WO2005 / 030731, WO2005 / 014553, USSN 10 / 957,251, WO2004 / 089911, WO02 / 081435, WO02 / 081433, WO03 / 018543, WO2004 / 031137, WO2004 / 031139, WO2004 / 031138, WO2004 / 101538, WO2004 / 101539, and WO02 / 47671 (including LY-450139).

[0108] In one embodiment, specific anti-cancer agents useful in the combination therapy of the present invention include, but are not limited to, the following: pembrolizumab (Keytruda®), abarelix (Plenaxisdepot®); aldesleukin (Prokine®); aldesleukin (Proleukin®); alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene Gel (Targretin®); Bleomycin (Blenoxane®); Bortezomib (Velcade®); Busulfan intravenous (Busulfex®); Busulfan oral (Myleran®); Calsterone (Methosarb®); Capecitabine (Xeloda®); Carboplatin (Paraplatin®); Carmustine (BCNU®, BiCNU®); Carmustine (Gliadel®); Carmustine and polipheprosan 20 Implants (GliadelWafer®); Celecoxib (Celebrex®); Cetuximab (Erbitux®); Chlorambucil (Leukeran®); Cisplatin (Platinol®); Cladribine (Leustatin®, 2-CdA®); Clofarabine (Clolar®); Cyclophosphamide (Cytoxan®, Neosar®); Cyclophosphamide (CytoxanInjection®); Cyclophosphamide (CytoxanTablet®); Cytarabine (Cytosar-U®);Cytarabine liposomal (DepoCyt®); Dacarbazine (DTIC-Dome®); Dactinomycin, Actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); Daunorubicin liposomal (DanuoXome®); Daunorubicin, daunomycin (Daunorubicin®); Daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); Dexrazoxane (Zinecard®); Docetaxel (Taxotere®); Doxorubicin (AdriamycinPFS®); Doxorubicin (Adriamycin®, Rubex®); Doxorubicin (Adriamycin PFS Injection®); Doxorubicin Liposomal (Doxil®); Dromostanolone propionate (Dromostanolone®); Dromostanolone propionate (Masterone injection®); Elliott's B Solution®; Epirubicin (Ellence®); Epoetin alfa (epogen®); Erlotinib (Tarceva®); Estramustine (Emcyt®); Etoposide phosphate (Etopophos®); Etoposide, VP-16 (Vepesid®); Exemestane (Aromasin®); Filgrastim (Neupogen®); Floxuridine (intra-arterial) (FUDR®); Fludarabine (Fludara®); Fluorouracil, 5-FU (Adrucil®); Fulvestrant (Faslodex®); Gefitinib (Iressa®); Gemcitabine (Gemzar®); Gemtuzumab ozogamicin (Mylotarg®); Goserelin acetate (Zoladex Implant®); Goserelin acetate (Zoladex®); Histrelin acetate (Histrelinimplant®);Hydroxyurea (Hydrea®); Ibritumomab tiucetan (Zevalin®); Idarubicin (Idamycin®); Ifosfamide (IFEX®); Imatinib mesylate (Gleevec®); Interferon alpha 2a (RoferonA®); Interferon alpha-2b (IntronA®); Irinotecan (Camptosar®); Lenalidomide (Revlimid®); Letrozole (Femara®); Leucovorin (Wellcovorin®) , Leucovorin®); leuprolide acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); mechlorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (M esnextabs®; methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); nofetumomab (Verluma®); opelvequin (Neumega®) )); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); Palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargas (Oncaspar®); pegfilgrastim (Neulasta®);Pemetrexed disodium (Alimta®); Pentostatin (Nipent®); Pipobroman (Vercyte®); Plicamycin, Mithramycin (Mithracin®); Porfimer sodium (Photofrin®); Procarbazine (Matulane®); Quinacrine (Atabrine®); Rasuburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; Sargramostim (Leukine®); Sargramostim (Prokine®); Sorafenib (Nexavar®); Streptozocin (Zanosar®); Sunitinib maleate (Suten t®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); tositumomab (Bexxar®); tositumomab / I-131 tositumomab (Bexxar®); trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); uracil mustard (Uracil Mustard Capsules®; valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); olaparib (Lynparza®), vorinostat (Zolinza®), and zoledronate (Zometa®), or pharma- ceutically acceptable salts thereof;

[0109] Thus, the scope of the present disclosure encompasses the use of a compound of the present disclosure in combination with a second compound selected from: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, PPAR-gamma agonists, PPAR-delta agonists, intrinsic multidrug resistance inhibitors, antiemetics, agents useful in the treatment of anemia, agents useful in the treatment of neutropenia, immune enhancing agents, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapy, gamma-secretase and / or NOTCH inhibitors, agents that inhibit receptor tyrosine kinases (RTKs), agents that inhibit cell cycle checkpoints, and any of the above therapeutic agents.

[0110] Yet another example of the present disclosure is a method of treating cancer, wherein the method comprises administering a therapeutically effective amount of a compound of the present disclosure in combination with paclitaxel or trastuzumab.

[0111] The therapeutic combinations disclosed herein can be used in combination with one or more other active agents, including, but not limited to, other anti-cancer agents used in the prevention, treatment, control, amelioration, or risk reduction of a particular disease or condition (e.g., cell proliferation disorder). In one embodiment, the compounds of the present disclosure are combined with one or more other anti-cancer agents for use in the prevention, treatment, control, amelioration, or risk reduction of a particular disease or condition for which the compounds of the present disclosure are useful. Such other active agents can be administered prior to, simultaneously with, or sequentially to the compounds of the present disclosure, by a route and in an amount commonly used therefor.

[0112] The present disclosure also encompasses pharmaceutical compositions useful for treating or preventing cancer comprising a therapeutically effective amount of a compound of the present disclosure and a second compound selected from the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, PPAR-gamma agonists, PPAR-delta agonists, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapy, gamma-secretase and / or NOTCH inhibitors, agents that inhibit receptor tyrosine kinases (RTKs), agents that inhibit cell cycle checkpoints, and any of the above therapeutic agents.

[0113] The disclosure further relates to a method of treating cancer in a human patient, the method comprising administering to the patient a PD-1 antagonist. The compound of the disclosure and the PD-1 antagonist can be administered simultaneously or sequentially.

[0114] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody independently selected from pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, atezolizumab (MPDL3280A), camrelizumab, and toripalimab. In other embodiments, the PD-L1 antagonist is an anti-PD-L1 antibody independently selected from atezolizumab, durvalumab, and avelumab.

[0115] In one embodiment, the PD-1 antagonist is pembrolizumab. In a particular subembodiment, the method comprises administering 200 mg of pembrolizumab to the patient about every 3 weeks. In another subembodiment, the method comprises administering 400 mg of pembrolizumab to the patient about every 6 weeks.

[0116] In a further subembodiment, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every 3 weeks. In a particular subembodiment, the patient is a pediatric patient.

[0117] In some embodiments, the PD-1 antagonist is nivolumab. In certain subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every 2 weeks. In other subembodiments, the method comprises administering 480 mg of nivolumab to the patient about every 4 weeks.

[0118] In some embodiments, the PD-1 antagonist is cemiplimab. In certain embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every three weeks.

[0119] In some embodiments, the PD-1 antagonist is atezolizumab. In certain subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every three weeks.

[0120] In some embodiments, the PD-1 antagonist is durvalumab. In certain subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every two weeks.

[0121] In some embodiments, the PD-1 antagonist is avelumab. In certain subembodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks.

[0122] When a compound of the present disclosure is administered in combination with an anti-human PD-1 antibody (or antigen-binding fragment thereof), the anti-human PD-1 antibody (or antigen-binding fragment thereof) can be administered simultaneously with the compound of the present disclosure, or before or after the compound of the present disclosure. The anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or any of the compounds of the present disclosure or pharma- ceutically acceptable salts thereof can be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as other agent(s). The weight ratio of the anti-human PD-1 antibody (or antigen-binding fragment thereof) to the compound of the present disclosure can vary and will depend on the therapeutically effective amount of each agent. Generally, a therapeutically effective amount of each is used. A combination comprising at least one anti-human PD-1 antibody (or antigen-binding fragment thereof), a compound of the present disclosure, and optionally other active agents, generally comprises a therapeutically effective amount of each active agent. In such combinations, the anti-human PD-1 antibody (or antigen-binding fragment thereof), the compound and other active agents may be administered separately or together. Moreover, the administration of one element may be prior to, concurrent with, or subsequent to the administration of the other agent(s).

[0123] In one embodiment, the disclosure provides an anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or a compound of the disclosure and at least one other active agent as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer.

[0124] The disclosure also provides for the use of a compound of the disclosure to treat cancer, where the patient has previously (e.g., within 24 hours) been treated with an anti-human PD-1 antibody (or antigen-binding fragment thereof).The disclosure also provides for the use of an anti-human PD-1 antibody (or antigen-binding fragment thereof) to treat a cell proliferative disorder, where the patient has previously (e.g., within 24 hours) been treated with an antibody-linker-payload compound (ADC) that is a compound of the disclosure.

[0125] The present disclosure further relates to a method of treating cancer, the method comprising administering to a subject in need of cancer treatment a combination therapy comprising (a) a compound of the present disclosure and (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof); wherein the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 21 days.

[0126] The present disclosure further relates to a method of treating cancer, the method comprising administering to a subject in need of cancer treatment a combination therapy comprising (a) a compound of the present disclosure and (b) an anti-human PD-1 antibody (or an antigen-binding fragment thereof). In certain embodiments, the cancer arises as one or more solid tumors or lymphomas. In further particular embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In yet another particular embodiment, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, MSI-H cancer, MMR-deficient cancer, non-small cell lung cancer, urothelial carcinoma, gastric or gastroesophageal junction adenocarcinoma, breast adenocarcinoma, and lymphoma. In further embodiments, the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma / leukemia, extranodal nasal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma / delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin's lymphoma. In certain embodiments, the cell proliferative disorder is a metastatic cancer, such as a liver metastasis from colon cancer. In further embodiments, the cell proliferative disorder is a cancer classified as stage III or stage IV cancer. In exemplary of these embodiments, the cancer is not surgically resectable.

[0127] In embodiments of the methods disclosed herein, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered by intravenous infusion or subcutaneous injection.

[0128] In one embodiment, the disclosure provides a composition comprising a compound of the disclosure, a pharma- ceutically acceptable carrier, and an anti-human PD-1 antibody (or an antigen-binding fragment thereof).

[0129] In another embodiment, the disclosure provides a composition comprising a compound of the disclosure, a pharma- ceutically acceptable carrier, and pembrolizumab.

[0130] In one embodiment, the disclosure provides a composition comprising a compound of the disclosure, a pharma- ceutically acceptable carrier, and two additional therapeutic agents, wherein one of the additional therapeutic agents is an anti-human PD-1 antibody (or an antigen-binding fragment thereof), and another of the additional therapeutic agents is independently selected from the group consisting of anti-cancer agents.

[0131] The compounds of the present disclosure can be used in combination with antiemetics to treat nausea or vomiting, including acute emesis, delayed emesis, late emesis, and anticipatory emesis, which may result from the use of the compounds of the present disclosure alone or in combination with radiation therapy. To prevent or treat emesis, the compounds of the present disclosure can be used in combination with other antiemetics, particularly neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (e.g., ondansetron, granisetron, tropisetron, and zatisetron), GABAB receptor agonists (e.g., baclofen), corticosteroids (e.g., dexamethasone, kenalog, aristocort, nasalide, prefelide, benecorten, or other drugs, such as those described in U.S. Pat. No. 2,789,633, or ... 118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712), antidopaminergics such as phenothiazines (e.g., prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide, aprepitant, fosaprepitant or dronabinol. In another example, combination therapy with an antiemetic selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for treating or preventing emesis that may occur upon administration of the compounds of the present disclosure.

[0132] The compounds of the present disclosure can also be administered with agents useful in the treatment of anemia, such as sustained erythropoiesis receptor activators (e.g., epoetin alpha).

[0133] The compounds of the present disclosure can also be administered together with agents useful in the treatment of neutropenia. Such neutropenia therapeutic agents are hematopoietic growth factors that regulate the production and function of neutrophils, such as human granulocyte colony-stimulating factor (G-CSF). An example of G-CSF is filgrastim.

[0134] The compounds of the present disclosure may be useful when co-administered with other therapeutic modalities, including, but not limited to, radiation therapy, surgery, and gene therapy. Thus, in one embodiment, the methods of treating cancer described herein may optionally include administration of an effective amount of radiation therapy, unless otherwise indicated. The radiation therapy is preferably gamma radiation.

[0135] The methods of treating cancer described herein can optionally include administration of an effective amount of radiation (i.e., the methods of treating cancer described herein can optionally include administration of radiation therapy).

[0136] Methods of treating cancer described herein include methods of treating cancer comprising administering a therapeutically effective amount of a compound of Formula IV in combination with radiation therapy and / or in combination with a second compound, wherein the second compound is selected from an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-gamma agonist, a PPAR-delta agonist, an intrinsic multidrug resistance inhibitor, an antiemetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immune enhancing agent, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapy, a gamma-secretase and / or NOTCH inhibitor, an agent that inhibits a receptor tyrosine kinase (RTK), an agent that inhibits a cell cycle checkpoint, and any of the above therapeutic agents.

[0137] Additional embodiments of the present disclosure include the pharmaceutical compositions, combinations, uses and methods described above, where it is understood that each embodiment may be combined with one or more other embodiments, provided such combinations are consistent with the description of the embodiment.Furthermore, the embodiments provided above are understood to encompass all embodiments, including those resulting from combinations of embodiments.

[0138] kit In one aspect, a kit is provided, wherein the kit comprises a therapeutically effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt, solvate, or ester of the compound, and a pharma- ceutically acceptable carrier, vehicle, or diluent.

[0139] In another aspect, a kit is provided that includes a specific amount of the disclosed compound and a specific amount of at least one additional therapeutic agent as described above, where the amount of the two or more active ingredients produces a desired therapeutic effect. In one embodiment, the disclosed compound and one or more additional therapeutic agents are provided in the same container. In one embodiment, the disclosed compound and one or more additional therapeutic agents are provided in separate containers.

[0140] The present disclosure includes within its scope prodrugs of the disclosed compounds. Typically, such prodrugs are functional derivatives of the disclosed compounds that can be readily converted in vivo to the required compound. Thus, in the disclosed therapeutic methods, the term "administration of a compound" or "administering a compound" includes treatment of the various conditions listed herein with a specifically disclosed compound or a compound not specifically disclosed but that can be converted in vivo to the specific compound after administration to a patient. General methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species that are generated upon introduction of the disclosed compounds into the biological environment.

[0141] The compounds described herein, or their pharma- ceutically acceptable salts and / or solvates, can be administered alone, in combination with other compounds of the present disclosure, and / or in cocktails in combination with other therapeutic agents. The choice of therapeutic agents that may be co-administered with the compounds of the present disclosure will depend, in part, on the condition being treated.

[0142] The compounds of the present disclosure may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration, and may be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals, the compounds of the present disclosure are effective for use in humans.

[0143] Pharmaceutical compositions for administering the compounds of the present disclosure may be advantageously provided in dosage unit form and may be prepared by methods known in the art of pharmacy. All methods include the step of mixing the active ingredient with a carrier consisting of one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers and / or finely divided solid carriers, and then, if necessary, shaping the product into the desired formulation. Pharmaceutical compositions contain an amount of active compound sufficient to produce the desired effect on the process or condition of a disease. The term "composition" as used herein is intended to include products containing specified amounts of specified ingredients and products resulting directly or indirectly from the combination of specified amounts of specified ingredients.

[0144] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to methods known in the art for preparing pharmaceutical compositions, and may incorporate one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives in said compositions to provide a medicamentously elegant and palatable preparation. Tablets contain the active ingredient mixed with non-toxic pharma-ceutically acceptable excipients suitable for the manufacture of tablets. Examples of such excipients may be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricants, such as magnesium stearate, stearic acid or talc. If the tablets are not coated, they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and provide a sustained action over a longer period of time. For example, sustained release materials (e.g., glyceryl monostearate or glyceryl distearate) may be used. They may be coated by the techniques described in U.S. Patents 4,256,105, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, fast dissolving tablets or fast dissolving films.

[0145] Oral formulations may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin); or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0146] Aqueous suspensions contain the active substance mixed with excipients suitable for producing aqueous suspensions. The excipients are suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia). Dispersing or wetting agents can be naturally occurring phospholipids (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0147] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or peanut oil) or in a mineral oil (e.g., liquid paraffin). The oily suspensions may also contain a thickening agent (e.g., beeswax, hard paraffin or acetyl alcohol). Sweetening and flavoring agents, as set forth above, may be incorporated to provide a tasteful oral preparation. The compositions may be preserved by the addition of an antioxidant (e.g., ascorbic acid).

[0148] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water contain the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents have already been mentioned above. Additional excipients, such as sweeteners, flavoring agents and coloring agents, may also be present.

[0149] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil (e.g., olive oil or arachis oil) and / or a mineral oil (e.g., liquid paraffin). Suitable emulsifiers may be naturally occurring gums (e.g., gum acacia or gum tragacanth), naturally occurring phospholipids (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of said partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening and flavoring agents.

[0150] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose, and may also contain a demulcent, a preservative, flavoring and coloring agents.

[0151] The pharmaceutical composition may take the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as a solvent or suspending medium. For this purpose, non-irritating fixed oils, including synthetic mono- or diglycerides, may be used. In addition, fatty acids (such as oleic acid) are used in the preparation of injectables.

[0152] The compounds of the present disclosure may also be administered in the form of suppositories for rectal administration of the drug. The composition may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. The materials are cocoa butter and polyethylene glycol.

[0153] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present disclosure are employed. Likewise, transdermal patches may also be used for topical application.

[0154] The pharmaceutical compositions and methods of the present disclosure may further include other therapeutically active compounds as described herein that are commonly used in the treatment of the above-mentioned pathological conditions.

[0155] In treating, preventing, controlling, ameliorating or reducing the risk of the conditions disclosed herein, suitable dosage levels of the compounds of the present disclosure are generally about 0.01-500 mg / kg of patient body weight per day, which may be administered in single or multiple doses. Suitable dosage levels may be about 0.01-250 mg / kg per day, about 0.05-100 mg / kg per day, or about 0.1-50 mg / kg per day. Doses within this range may be 0.05-0.5, 0.5-5, or 5-50 mg / kg per day. For oral administration, the composition may be provided in the form of a tablet containing 1.0-1000 mg of active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 mg of active ingredient, in order to symptomatically adjust the dosage to the patient being treated. The compound may be administered on a regimen of 1-4 times per day, or may be administered 1-2 times per day.

[0156] However, the specific dose level and frequency of administration for a particular patient may vary and will depend on a variety of factors including the activity of the specific compound used, the metabolic stability and duration of action of that compound, the age, body weight, general health, sex, diet, mode of administration, time of administration, excretion rate, drug combination, the severity of the specific condition and the host being treated.

[0157] Methods for preparing the compounds of this disclosure are illustrated in the following schemes and examples. Starting materials are made according to procedures known in the art or as illustrated herein. EXAMPLES

[0158] Preparation Examples The compounds of the present disclosure can be prepared according to the following schemes and specific examples or variants thereof using readily available starting materials, reagents and conventional synthesis procedures. In addition, it is also possible to use variants that are known per se to those skilled in the art but are not mentioned in detail. The general procedures for preparing the compounds claimed in the present disclosure can be easily understood by those skilled in the art by looking at the following schemes and descriptions. Abbreviations used in the experiments include, but are not limited to, the following:

[0159] [Table 1] TIFF2025511436000024.tif105161

[0160] General Experimental Information: All reactions were magnetically stirred unless otherwise indicated. All reagents and solvents were purchased from commercial sources and used as received unless otherwise indicated. Reaction progress and analysis of synthetic intermediates were assessed by LCMS (UV detection by ESI, APCI, or other mass detection) using gradients of MeCN / water (with either TFA, formic acid, or NH4HCO3 modifiers) where applicable. Silica gel column chromatography and reversed-phase flash column chromatography were performed using commercially available prepacked columns. Reverse-phase preparative HPLC purification was performed on a preparative HPLC instrument equipped with a UV detector and a MS detector using gradients of MeCN / water (with either TFA, formic acid, or NH4OH modifiers). 1 H NMR spectra were collected at room temperature, chemical shifts are reported in ppm relative to the residual proteo-solvent signal, and multiplicities, coupling constants (if applicable) and signal integrals are given in brackets. All ECs listed in the tables are 50Data refers to the CellTiter-Glo® 2.0 cytotoxicity assay described in the Biological Assays section.

[0161] Synthetic Schemes, Intermediates and Examples The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following general synthetic schemes and specific preparative examples. Starting materials are either commercially available or can be prepared by known methods.

[0162] Example 1 Preparation of Compound 1 [ka] To a solution of (R)-3-hydroxydihydrofuran-2(3H)-one (1b, 200 mg, 2.0 mmol) in MeOH (0.20 mL) and DMF (0.40 mL) was added a mixture of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 0.40 mL, 0.12-0.16 mmol, ca. 0.35-0.40 M in DMF (containing Hunig's base)). The reaction was heated to 70° C. overnight for 5 nights. The mixture was cooled to room temperature, filtered through a syringe filter, and then subjected to reverse phase column chromatography (25-60% MeCN / water (with 0.1% formic acid modifier)) to give (R)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxybutanamide (1) as a solid (peak 1 desired product, a small amount of isomeric product (peak 2) was also detected).

[0163] MS: m / z = 538 [M+H]. 1 H NMR (500 MHz, DMSO-d6): δ 8.44 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 11.0 Hz, 1H), 7.30 (s, 1H), 6.52 (s, 1H), 5.59 - 5.54 (m, 1H), 5.41 (s, 2H), 5.24 - 5.07 (m, 2H), 4.11 (dd, J = 9.1, 3.4 Hz, 1H), 3.59 - 3.54 (m, 2H), 3.25 - 3.08 (m, 3H), 2.38 (s, 3H), 2.23 - 2.10 (m, 2H), 2.03 - 1.94 (m, 1H), 1.91 - 1.74 (m, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0164] The following compounds of the present disclosure in Table 1 were prepared using methods similar to those described in Example 1, varying the reaction time (2-3 days and 60-65° C.) and substituting the appropriate reactants and / or reagents:

[0165] [Table 2]

[0166] Intermediate I-1c Preparation of intermediate I-1c [ka] Step A - Synthesis of Intermediate I-1a To a solution of (R)-3-hydroxydihydrofuran-2(3H)-one (1b, 2.2 g, 22 mmol) in MeOH (20 mL) was added Dowex 50W X8 (hydrogen form, strong acid), 200-400 mesh resin (1.1 g). The reaction was stirred at room temperature for 2 h 20 min. The mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resulting methyl (R)-2,4-dihydroxybutanoate (I-1a) was used directly as an oil in the next reaction. 1 H NMR (500 MHz, CDCl3): δ 4.40 (dd, J = 7.8, 3.9 Hz, 1H), 3.91 - 3.81 (m, 2H), 3.81 (s, 3H), 2.13 - 2.04 (m, 1H), 1.96 - 1.88 (m, 1H).

[0167] Step B - Synthesis of Intermediate I-1b To a mixture of methyl (R)-2,4-dihydroxybutanoate (I-1a, 2.0 g, 15 mmol) and potassium acetate (6.0 g, 61 mmol) in DCM (10 mL) and water (10 mL) was added (bromodifluoromethyl)trimethylsilane (4.0 mL, 26 mmol). The reaction was stirred vigorously at room temperature for 3 days. The mixture was diluted with saturated NaHCO3, DCM and 3:1 CHCl3:IPA (100 mL). The resulting mixture was shaken and then passed through a hydrophobic membrane phase separator. The remaining aqueous layer was re-extracted with 3:1 CHCl3:IPA (100 mL) and the mixture was also passed through a hydrophobic membrane phase separator. The organic layers were combined and concentrated under reduced pressure. The crude material was subjected to silica gel column chromatography (0-100% EtOAc / Hexanes) to afford methyl (R)-4-(difluoromethoxy)-2-hydroxybutanoate (I-1b) as an oil.

[0168] 1 H NMR (500 MHz, CDCl3) δ 6.18 (t, J = 74.9 Hz, 1H), 4.35 - 4.29 (m, 1H), 4.06 - 3.98 (m, 2H), 3.81 (s, 3H), 2.85 (d, J = 4.9 Hz, 1H), 2.20 - 2.13 (m, 1H), 2.02 - 1.93 (m, 1H).

[0169] Step C - Synthesis of Intermediate I-1c To a solution of methyl (R)-4-(difluoromethoxy)-2-hydroxybutanoate (I-1b, 19 mg, 0.10 mmol) in DCE (2.0 mL) was added trimethyltin hydroxide (75 mg, 0.41 mmol). The reaction was stirred at 60° C. overnight. The mixture was cooled, diluted with EtOAc and 1 M HCl, and shaken. The organic layer was separated and passed through a hydrophobic membrane phase separator. The organic layer was then concentrated under reduced pressure. The resulting (R)-4-(difluoromethoxy)-2-hydroxybutanoic acid (I-1c) was used directly unpurified in the next step as described in Example 3.

[0170] Intermediate I-2d Preparation of intermediate I-2d [ka] Step A - Synthesis of Intermediate I-2b To a mixture of 3-(tert-butoxy)-2-cyclopropyl-3-oxopropanoic acid (I-2a, 0.10 g, 0.50 mmol) and CDI (0.12 g, 0.75 mmol) was added DCM (2.0 mL). The reaction was stirred at room temperature overnight. The reaction was diluted with DCM and water, extracted, and then passed through a hydrophobic membrane phase separator. The organic layer was concentrated under reduced pressure to give crude tert-butyl 2-cyclopropyl-3-(1H-imidazol-1-yl)-3-oxopropanoate (I-2b), which was used directly in the next reaction.

[0171] 1 H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.49 (s, 1H), 7.11 (s, 1H), 3.08 (d, J = 9.7 Hz, 1H), 1.60 - 1.52 (m, 1H), 1.42 (s, 9H), 0.82 - 0.72 (m, 2H), 0.53 - 0.46 (m, 1H), 0.30 - 0.24 (m, 1H). Step B - Synthesis of Intermediate I-2c To a solution of NaBH4 (0.060 g, 1.5 mmol) in THF (2.0 mL) and water (1.5 mL) was added dropwise a solution of tert-butyl 2-cyclopropyl-3-(1H-imidazol-1-yl)-3-oxopropanoate (I-2b, 0.13 g, 0.5 mmol) in THF (2.0 mL). The reaction was stirred at room temperature overnight. The reaction was then diluted with DCM, water and 1M HCl (3.0 mL). The mixture was extracted and passed through a hydrophobic membrane phase separator. The organic layer was concentrated under reduced pressure to give crude tert-butyl 2-cyclopropyl-3-hydroxypropanoate (I-2c), which was used directly in the next reaction.

[0172] 1 H NMR (500 MHz, CDCl3) δ 3.86 - 3.78 (m, 2H), 1.74 - 1.68 (m, 1H), 1.48 (s, 9H), 0.95 - 0.86 (m, 1H), 0.57 - 0.52 (m, 2H), 0.40 - 0.35 (m, 1H), 0.20 - 0.16 (m, 1H). Step C - Synthesis of Intermediate I-2d To a solution of tert-butyl 2-cyclopropyl-3-hydroxypropanoate (I-2c, 0.090 g, 0.50 mmol) in DCM (4.0 mL) was added HCl (0.40 mL, 1.6 mmol, 4.0 M in dioxane). The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the resulting crude 2-cyclopropyl-3-hydroxypropanoic acid (I-2d) was used directly in the next step as described in Example 3.

[0173] Intermediate I-3d and Intermediate I-3e Preparation of Intermediate I-3d and Intermediate I-3e [ka] SFC separation of the enantiomers to give I-3b and I-3c Racemic 2-(((benzyloxy)carbonyl)amino)-3,3-difluoro-2-methylpropanoic acid (I-3a, 1.2 g, 4.4 mmol) was subjected to preparative chiral SFC (AD-H 2×25 cm, 10%(EtOH+0.1%DEA) / CO2, 100 bar, 70 mL / min) to give Enantiomer 1 (Peak 1, 95% ee, absolute configuration unknown) and Enantiomer 2 (Peak 2, 99% ee, absolute configuration unknown) as diethylamine salts.

[0174] To obtain the free acid, the diethylamine salt of enantiomer 1 was dissolved in EtOAc and shaken with aqueous 1M HCl. The organic layer was back-extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(((benzyloxy)carbonyl)amino)-3,3-difluoro-2-methylpropanoic acid (I-3b, enantiomer 1, absolute configuration unknown).

[0175] 1 H NMR (500 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.10 (s, 1H), 7.42 - 7.27 (m, 5H), 6.28 (t, J = 56.1 Hz, 1H), 5.03 (s, 2H), 1.34 (s, 3H).

[0176] The free acid of 2-(((benzyloxy)carbonyl)amino)-3,3-difluoro-2-methylpropanoic acid (I-3c, enantiomer 2, absolute configuration unknown) was obtained in a similar manner.

[0177] Step A - Synthesis of Intermediate I-3d and Intermediate I-3e A mixture of 2-(((benzyloxy)carbonyl)amino)-3,3-difluoro-2-methylpropanoic acid (I-3b, enantiomer 1, 290 mg, 1.1 mmol), 10 wt% Pd / C (430 mg, 0.41 mmol Pd) and MeOH (20 mL) was stirred under H2 (1 atm) overnight. The reaction mixture was then filtered through Celite®, rinsing with MeOH and DCM, followed by removal of the solvent under reduced pressure to give 2-amino-3,3-difluoro-2-methylpropanoic acid (I-3d, enantiomer 1, absolute configuration unknown) as a solid.

[0178] 1 H NMR (500 MHz, DMSO-d6) δ 7.71 (br s, 3H), 6.18 (t, J = 54.4 Hz, 1H), 1.27 (s, 3H).

[0179] 2-Amino-3,3-difluoro-2-methylpropanoic acid (I-3e, enantiomer 2, absolute configuration unknown) was obtained in a similar manner from I-3c.

[0180] Intermediate I-4b Preparation of intermediate I-4b [ka] A mixture of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine (I-4a, 31 mg, 0.10 mmol), HATU (36 mg, 0.095 mmol), and Hunig's base (18 μL, 0.10 mmol) in DMF (0.50 mL) was stirred at room temperature for 2 min, at which point 2-amino-3,3-difluoro-2-methylpropanoic acid (I-3d, 14 mg, 0.10 mmol) and additional Hunig's base (18 μL, 0.10 mmol) were added. The reaction mixture was stirred at room temperature for 1 h and then subjected to reverse phase column chromatography (20-60% MeCN / HO (with 0.1% formic acid modifier)) to afford 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-3,3-difluoro-2-methylpropanoic acid (I-4b) as a solid.

[0181] MS: m / z = 455 [M+Na]. 1 H NMR (500 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.47 (s, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.73 (t, J = 7.6 Hz, 2H), 7.53 (s, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 6.29 (t, J = 58.5 Hz, 1H), 4.31 - 4.17 (m, 3H), 4.15 - 4.04 (m, 1H), 1.37 (s, 3H), 1.21 (d, J = 7.1 Hz, 3H).

[0182] Intermediate I-5b Preparation of intermediate I-5b [ka] Step A - Synthesis of Compound I-5b A stirred solution of 1,1-difluoropropan-2-ol (I-5a, 0.21 mL, 2.5 mmol) in DCM (1.2 mL) at -78 °C was successively treated with triethylamine (1.1 mL, 7.5 mmol) and nonafluorobutanesulfonyl fluoride (0.76 mL, 4.3 mmol). The reaction mixture was allowed to warm gradually to room temperature and continued to stir at room temperature overnight. The mixture was then poured into aqueous Na2CO3 and extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give 1,1-difluoropropan-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (I-5b), which was used directly without purification.

[0183] Example 2 Preparation of compound 4 [ka] To a solution of 2,3-dihydroxy-2-methylpropanoic acid (4a, 11 mg, 0.090 mmol) in DMF (380 μL) was added (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 200 μL, 0.070-0.08 mmol, ca. 0.35-0.40 M in DMF (containing 3.0 eq. EtN), HATU (34 mg, 0.090 mmol) and DIPEA (39 μL, 0.23 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The mixture was then directly purified by reverse-phase column chromatography (20-60% MeCN / water with 0.1% formic acid modifier) ​​to give N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,3-dihydroxy-2-methylpropanamide (4, peak 2) as a solid.

[0184] MS: m / z = 538 [M+H]. 1 H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 10.9 Hz, 1H), 7.30 (s, 1H), 5.54 - 5.50 (m, 1H), 5.42 (s, 2H), 5.28 (d, J = 19.1 Hz, 1H), 5.16 (d, J = 19.1 Hz, 1H), 3.64 (d, J = 10.7 Hz, 1H), 3.39 (d, J = 10.7 Hz, 1H), 3.16 (br t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 2.25 - 2.19 (m, 1H), 2.15 - 2.08 (m, 1H), 1.90 - 1.81 (m, 2H), 1.24 (s, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0185] The following compounds of the present disclosure in Table 2 were prepared using methods similar to those described in Example 2, varying reaction times (from 10 minutes to 1 hour) and substituting the appropriate reactants and / or reagents:

[0186] [Table 3] TIFF2025511436000034.tif232126TIFF2025511436000035.tif218124TIFF2025511436000036.tif59162

[0187] Example 3 Preparation of compound 21 [ka] A solution of (R)-4-(difluoromethoxy)-2-hydroxybutanoic acid (I-1c, 18 mg, 0.10 mmol), HATU (39 mg, 0.10 mmol), and N-methylmorpholine (0.020 mL, 0.18 mmol) in DMF (1 mL) was stirred at room temperature for about 10 min, followed by addition of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 0.25 mL, 0.089-0.10 mmol, ca. 0.35-0.40 M (3.0 eq.) in DMF. A mixture of (R)-4-(difluoromethoxy)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxybutanamide (21) was added as a solid. The reaction was stirred at room temperature for approximately 1 hour and 40 minutes. The material was filtered and then subjected to reverse phase column chromatography (25-70% MeCN / water (with 0.1% formic acid modifier)) to give (R)-4-(difluoromethoxy)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxybutanamide (21) as a solid.

[0188] MS: m / z = 588 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 8.53 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 10.7 Hz, 1H), 7.31 (s, 1H), 6.68 (t, J = 76.3 Hz, 1H, partially overlaps with doublet at 6.51 ppm), 6.51 (d, J = 5.5 Hz, 1H, partly overlaps with triplet at 6.68 ppm), 5.77 (d, J = 5.8 Hz, 1H), 5.61 - 5.54 (m, 1H), 5.42 (s, 2H), 5.25 - 5.12 (m, 2H), 4.11 - 4.05 (m, 1H), 4.01 - 3.94 (m, 2H), 2.40 (s, 3H), 2.23 - 2.11 (m, 3H), 2.03 - 1.92 (m, 2H), 1.92 - 1.81 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0189] The following compounds of the present disclosure in Table 3 were prepared using methods similar to those described in Example 3, varying reaction times (up to 4 hours) and substituting the appropriate reactants and / or reagents:

[0190] [Table 4]

[0191] Example 4 Preparation of compound 24 [ka] A solution of 3-hydroxy-2,2-dimethylpropanoic acid (24a, 22 mg, 0.19 mmol) in DMF (380 μL) was mixed with DIPEA (99 μL, 0.56 mmol) and (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 250 μL, 0.089-0.10 mmol, ca. 0.35-0.40 M (3.0 eq.) in DMF). Et3N) was added, followed by 1-propanephosphonic anhydride solution in DMF (150 μL, 0.25 mmol). The resulting mixture was stirred overnight at room temperature and then purified by reverse phase column chromatography (5-60% MeCN / water (with 0.1% formic acid modifier)) to give N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2,2-dimethylpropanamide (24) as a solid.

[0192] MS: m / z = 536 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 11.0 Hz, 1H), 7.31 (s, 1H), 6.51 (s, 1H), 5.60 - 5.53 (m, 1H), 5.42 (s, 2H), 5.26 - 5.12 (m, 2H), 4.87 (t, J = 5.1 Hz, 1H), 3.45 (dd, J = 10.4, 5.0 Hz, 1H), 3.38 (dd, J = 10.5, 4.9 Hz, 1H), 3.18 - 3.12 (m, 2H), 2.40 (s, 3H), 2.20 - 2.06 (m, 2H), 1.92 - 1.80 (m, 2H), 1.11 (d, J = 9.8 Hz, 6H), 0.87 (t, J = 7.3 Hz, 3H).

[0193] The following compounds of the present disclosure in Table 4 were prepared using methods similar to those described in Example 4, varying reaction times (15 minutes to overnight) and substituting the appropriate reactants and / or reagents:

[0194] [Table 5]

[0195] Example 5 Preparation of compound 28 [ka] Step A - Synthesis of Compound 28b To a solution of methyl (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (28a, 0.15 g, 0.94 mmol) in DCE (3.0 mL) was added trimethyltin hydroxide (0.25 g, 1.4 mmol). The reaction was stirred at 80° C. for 2.5 h. The mixture was cooled and diluted with EtOAc and dilute aqueous HCl (1.5 mmol). After shaking the mixture, the organic layer was separated, passed through a hydrophobic membrane phase separator, and concentrated under reduced pressure to give (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (28b) as an oil, which was used directly in the next reaction unpurified.

[0196] Step B - Synthesis of Compound 28 To a solution of (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (28b, 22 mg, 0.15 mmol) in DMF (1.0 mL) was added Hunig's base (0.050 mL, 0.29 mmol) followed by HATU (57 mg, 0.15 mmol). The reaction was stirred at room temperature for 10 minutes and then a mixture of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 0.30 mL, 0.11-0.12 mmol, ca. 0.35-0.40 M in DMF (containing Hunig's base)) was added. The reaction was stirred at room temperature for 1 hour 40 minutes, then another portion of (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (30 mg, 0.21 mmol), HATU (70 mg, 0.18 mmol), and Hunig's base (0.050 mL, 0.29 mmol) in DMF (0.30 mL) was added. The reaction was stirred at room temperature for 20 minutes. Then HCl (0.20 mL, 0.80 mmol, 4.0 M in dioxane) in water (0.20 mL) was added and the reaction was stirred overnight at room temperature. Another portion of HCl (0.20 mL, 4.0 M in dioxane) was added, and after 2 hours 20 minutes the final portion of HCl (0.10 mL, 4.0 M in dioxane) was added. The reaction was stirred at room temperature for an additional 4.5 hours. The mixture was then filtered and subjected to reverse phase column chromatography (25-60% MeCN / water with 0.1% formic acid modifier) ​​to give (1S,9S)-1-((S)-2,3-dihydroxypropanamido)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-7-ium hexafluorophosphate (V) (28, peak 1, PF6 salt) as a solid.

[0197] MS: m / z = 524 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 10.9 Hz, 1H), 7.31 (s, 1H), 6.52 (s, 1H), 5.57 - 5.51 (m, 1H), 5.47 (d, J = 5.6 Hz, 1H), 5.42 (s, 2H), 5.22 (q, J = 18.9 Hz, 2H), 4.72 (t, J = 5.7 Hz, 1H), 4.03 - 3.99 (m, 1H), 3.66 - 3.60 (m, 1H), 3.57 - 3.51 (m, 1H), 3.23 - 3.10 (m, 2H), 2.40 (s, 3H), 2.27 - 2.19 (m, 1H), 2.12 (d, J = 4.7 Hz, 1H), 1.92 - 1.81 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).

[0198] The following compounds of the present disclosure in Table 5 were prepared using methods similar to those described in Example 5, substituting the appropriate reactants and / or reagents:

[0199] [Table 6]

[0200] Example 6 Preparation of compound 30 [ka] Step A - Synthesis of Compound 30b A mixture of 2-(1-((benzyloxy)methyl)cyclopropyl)acetic acid (30a, 3.0 g, 14 mmol), MeOH (23 mL), and sulfuric acid (16 mL, 0.31 mmol) was stirred at room temperature for 3 days. The solvent was removed under reduced pressure. The residue was treated with DCM and water, then neutralized to pH 7 with sodium bicarbonate. The two layers were separated and the aqueous layer was washed twice more with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give crude methyl 2-(1-((benzyloxy)methyl)cyclopropyl)acetate (30b) as an oil.

[0201] Step B - Synthesis of Compound 30c To a stirred solution of KHMDS (3.8 mL, 1.9 mmol, 0.5 M in toluene) at −78° C. under argon was added dropwise a solution of methyl 2-(1-((benzyloxy)methyl)cyclopropyl)acetate (30b, 300 mg, 1.3 mmol) in THF (4.0 mL). The reaction mixture was stirred at −78° C. for 30 min at which time a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (502 mg, 1.9 mmol) in THF (2.0 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min, then quenched with isopropanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc / hexanes) to give methyl 2-(1-((benzyloxy)methyl)cyclopropyl)-2-hydroxyacetate (30c).

[0202] Step C - Synthesis of Compound 30d A mixture of 2-(1-((benzyloxy)methyl)cyclopropyl)-2-hydroxyacetate (30c, 100 mg, 0.40 mmol), 10 wt% Pd / C (21 mg, 0.020 mmol Pd) and MeOH (2.0 mL) was stirred under H2 (1.0 atm) overnight. The reaction mixture was then filtered through Celite® and rinsed with MeOH. The solvent was removed under reduced pressure to give crude 7-hydroxy-5-oxaspiro[2.4]heptan-6-one (30d). This crude mixture was used directly in the next step.

[0203] Step D - Synthesis of Compound 30e A mixture of crude 7-hydroxy-5-oxaspiro[2.4]heptan-6-one (30d, 51 mg, 0.40 mmol), lithium hydroxide (9.6 mg, 0.40 mmol), and anhydrous MeOH (1.6 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was treated with DMF (1.6 mL), imidazole (123 mg, 1.8 mmol), and tert-butylchlorodimethylsilane (133 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 3 days. After removing the solvent under reduced pressure, the mixture was diluted with EtOAc and washed with aqueous 1 M HCl. The aqueous layer was back-extracted twice more with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give crude 2-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-2-hydroxyacetic acid (30e) as an oil. This was used directly in the next step.

[0204] Step E - Synthesis of Compound 30f A mixture of crude 2-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-2-hydroxyacetic acid (30e, 84 mg, 0.32 mmol) and Hunig's base (73 μL, 0.42 mmol) with (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 380 μL, 0.13-0.15 mmol, ca. 0.35-0.40 M (3.0 eq.) in DMF was added. To a stirred mixture of EtN (containing 1,2-dichlorophenyl)-2-( ...

[0205] Step F - Synthesis of Compound 30 A mixture of crude 2-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxyacetamide (30f, 10 mg, 0.015 mmol), TFA (18 μL, 0.23 mmol), DMF (300 μL, 0.42 mmol), and MeOH (100 μL) was stirred at room temperature for 5 h. The resulting suspension was then solubilized in DMSO and subjected to reverse phase column chromatography (10-100% MeCN / HO with 0.1% formic acid modifier) ​​to give N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxy-2-(1-(hydroxymethyl)cyclopropyl)acetamide (30, 1:1 mixture of diastereomers) as a solid.

[0206] MS: m / z = 564 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.79 (apparent t, J = 11.7 Hz, 2H), 7.31 (s, 2H), 6.52 (s, 2H), 5.64 - 5.51 (m, 2H), 5.42 (s, 4H), 5.31 - 5.07 (m, 4H), 4.26 (d, J = 11.0 Hz, 1H), 3.90 (s, 1H), 3.77 (s, 1H), 3.44 (s, 2H, overlapping with water peak), 3.23 - 3.11 (m, 5H), 2.41 (s, 3H), 2.40 (s, 3H), 2.27 - 2.05 (m, 4H), 1.93 - 1.78 (m, 4H), 0.92 - 0.83 (m, 6H), 0.78 - 0.72 (m, 1H), 0.70 - 0.60 (m, 3H), 0.55 - 0.46 (m, 2H), 0.45 - 0.37 (m, 2H).

[0207] Example 7 Preparation of compound 31 [ka] Step A - Synthesis of Compound 31a A mixture of (R)-3-hydroxydihydrofuran-2(3H)-one (1b, 600 mg, 5.9 mmol), methyl iodide (1.8 mL, 29 mmol), silver oxide (1.5 g, 6.6 mmol), and acetonitrile (12 mL) was stirred overnight at 75° C. in the dark under argon. The mixture was then filtered through Celite®, rinsed with acetonitrile, and the solvent was removed under reduced pressure. The residue was redissolved in DCM, filtered again, and concentrated under reduced pressure to give crude (R)-3-methoxydihydrofuran-2(3H)-one (31a) as an oil.

[0208] Step B - Synthesis of Compound 31b A mixture of (R)-3-methoxydihydrofuran-2(3H)-one (31a, 350 mg, 3.0 mmol), lithium hydroxide (76 mg, 3.2 mmol), and methanol (6.0 mL) was stirred at room temperature for 3 days. The solvent was then thoroughly removed under reduced pressure. To the resulting residue was added DMF (6.0 mL), imidazole (620 mg, 9.0 mmol), and tert-butylchlorodimethylsilane (590 mg, 3.9 mmol). The reaction mixture was stirred at room temperature overnight, at which point the majority of the solvent was removed under reduced pressure. The residue was diluted with DCM and washed with 1 M aqueous HCl. The aqueous layer was back-extracted twice more with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give crude (R)-4-((tert-butyldimethylsilyl)oxy)-2-methoxybutanoic acid (31b) as an oil. This was used directly in the next step.

[0209] Step C - Synthesis of Compound 31 (1S,9S)-9-Ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-1-aminium methanesulfonate (1a, 290 μL, 0.10-0.12 mmol, approximately 0.35-0.40 M (3.0 eq.) in DMF To a stirred mixture of (R)-4-((tert-butyldimethylsilyl)oxy)-2-methoxybutanoic acid (31b, 140 mg, 0.57 mmol), Hunig's base (35 μL, 0.20 mmol) and DMF (0.10 mL) was added HATU (65 mg, 0.17 mmol). The mixture was stirred at room temperature for 10 min, at which point MeOH (0.10 mL) and TFA (77 μL, 1.0 mmol) were added. The mixture was stirred at room temperature for 2 h. The resulting suspension was then diluted with DMSO (0.30 mL) and subjected to reverse phase column chromatography (10-70% MeCN / HO (with 0.1% formic acid modifier)) to give (R)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methoxybutanamide (31) as a solid.

[0210] MS: m / z = 552 [M+H]. 11H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 10.9 Hz, 1H), 7.29 (s, 1H), 6.51 (s, 1H), 5.64 - 5.54 (m, 1H), 5.41 (s, 2H), 5.12 (s, 2H), 4.54 (s, 1H), 3.82 (dd, J = 8.5, 4.4 Hz, 1H), 3.51 (t, J = 6.3 Hz, 2H), 3.31 (s, 3H), 3.24 - 3.09 (m, 2H), 2.37 (s, 3H), 2.21 - 2.09 (m, 2H), 1.94 - 1.75 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H).

[0211] Example 8 Preparation of compound 32

Chem.

[0212] MS: m / z = 522 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 8.38 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 11.0 Hz, 1H), 7.29 (s, 1H), 6.52 (s, 1H), 5.60 - 5.53 (m, 1H), 5.42 (s, 2H), 5.21 (s, 2H), 4.62 (s, 1H), 3.61 - 3.51 (m, 1H), 3.36 - 3.34 (m, 1H), 3.22 - 3.10 (m, 2H), 2.47 - 2.40 (m, 1H), 2.38 (s, 3H), 2.20 - 2.05 (m, 2H), 1.94 - 1.79 (m, 2H), 1.01 (d, J = 6.9 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0213] The following compounds of the present disclosure in Table 6 were prepared using methods similar to those described in Example 8, varying reaction times (2 hours for the LiOH step, 15-30 minutes for the coupling step) and substituting the appropriate reactants and / or reagents:

[0214] [Table 7] TIFF2025511436000047.tif54144

[0215] Example 9 Preparation of compound 38 [ka] Step A - Synthesis of Compound 38b To a mixture of 3,3-dimethyldihydrofuran-2(3H)-one (38a, 0.068 g, 0.60 mmol) and lithium hydroxide (0.014 g, 0.60 mmol) was added ethanol (2.0 mL). The reaction was heated to 60° C. overnight. The reaction was cooled and concentrated under reduced pressure. The crude lithium 4-hydroxy-2,2-dimethylbutanoate (38b) obtained as a solid was used directly in the next reaction.

[0216] Step B - Synthesis of Compound 38c To a mixture of lithium 4-hydroxy-2,2-dimethylbutanoate (38b, 0.079 g, 0.60 mmol), DMAP (7.0 mg, 0.060 mmol), and TBSCl (0.10 g, 0.66 mmol) in DMF (3.0 mL) was added TEA (0.10 mL, 0.72 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with DCM, water, and 1 M HCl (1.5 mL). The mixture was extracted and passed through a hydrophobic membrane phase separator. The organic layer was concentrated under reduced pressure to give crude 4-((tert-butyldimethylsilyl)oxy)-2,2-dimethylbutanoic acid (38c), which was used directly in the next reaction.

[0217] Step C - Synthesis of Compound 38 To a solution of 4-((tert-butyldimethylsilyl)oxy)-2,2-dimethylbutanoic acid (38c, 150 mg, 0.60 mmol) and N-methylmorpholine (0.050 mL, 0.46 mmol) in DMF (1.0 mL) was added HATU (170 mg, 0.45 mmol). The reaction was stirred at room temperature for 5 minutes, and then (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 0.30 mL, 0.11-0.12 mmol, ca. 0.35-0.40 M in DMF (containing 3.0 eq. Et3N)) mixture was added. The reaction was stirred at room temperature for 2 hours and 40 minutes. MeOH (0.15 mL) was then added, followed by TFA (0.20 mL). The reaction was stirred at room temperature for 1 hour. TEA (0.30 mL) was then added and the mixture was filtered and subjected to reverse phase column chromatography (25-65% MeCN / water (with 0.1% formic acid modifier)) to give N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2,2-dimethylbutanamide (38) as a solid.

[0218] MS: m / z = 550 [M+H]. 1H NMR (500 MHz, DMSO-d6): δ 8.07 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 10.9 Hz, 1H), 7.31 (s, 1H), 5.60 - 5.54 (m, 1H), 5.42 (s, 2H), 5.22 - 5.08 (m, 2H), 3.46 - 3.41 (m, 4H) (broad water peak overlapping signal), 3.20 - 3.11 (m, 3H) (broad water peak overlapping signal), 2.40 (s, 3H), 2.16 - 2.06 (m, 2H), 1.90 - 1.81 (m, 2H), 1.72 (t, J = 7.4 Hz, 2H), 1.17 (d, J = 6.6 Hz, 6H), 0.88 (t, J = 7.3 Hz, 3H).

[0219] Example 10 Preparation of Compound 39 and Compound 40 [ka] Step A - Synthesis of Compound 39b To a stirred mixture of NaH (4.7 g, 120 mmol, 60 wt%) in hexane (100 mL) at room temperature was added dihydrofuran-2(3H)-one (39a, 10 g, 116 mmol) and ethyl formate (8.6 g, 120 mmol) dropwise. After about 10% of the mixture had been added, a small amount of absolute ethanol (0.70 mL) was added to initialize the reaction, and the mixture was then refluxed at 70° C. for 2 h. The mixture was filtered, and the filter cake was washed with hexane (60 mL) and dried under reduced pressure to give crude sodium (Z)-(2-oxodihydrofuran-3(2H)-ylidene)methanolate (39b) as a solid, which was used directly in the next reaction.

[0220] Step B - Synthesis of Compound 39c Sodium (Z)-(2-oxodihydrofuran-3(2H)-ylidene)methanolate (39b, 15 g, 110 mmol) (freshly prepared) in CHI (43 mL) was heated to reflux (60° C.) under nitrogen for 48 h in a round-bottom flask equipped with a reflux condenser. The reaction mixture was cooled to room temperature and filtered. The flask and filter residue were washed with chloroform (CHCl3) and the combined filtrate was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (1:1 petroleum ether:EtOAc) to give 3-methyl-2-oxotetrahydrofuran-3-carbaldehyde (39c) as an oil.

[0221] Step C - Synthesis of Compound 39d To a solution of 3-methyl-2-oxotetrahydrofuran-3-carbaldehyde (39c, 6.0 g, 47 mmol) in DCM (60 mL) was added DAST (19 mL, 140 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 18 h. The mixture was added to saturated aqueous NaHCO3 (300 mL), then the pH was adjusted to 8 and the mixture was extracted with DCM (3×60 mL). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give crude 3-(difluoromethyl)-3-methyldihydrofuran-2(3H)-one (39d) as an oil. This material was used directly in the next step.

[0222] Step D - Synthesis of Compound 39e To a stirred mixture of 3-(difluoromethyl)-3-methyldihydrofuran-2(3H)-one (39d, 2.0 g, 13 mmol) in MeOH / THF / water (1:1:1) (10 mL) at room temperature was added LiOH (0.96 g, 40 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure to give crude lithium 2-(difluoromethyl)-4-hydroxy-2-methylbutanoate (39e) as a solid, which was used directly in the next step.

[0223] Step E - Synthesis of Compound 39f To a stirred mixture of imidazole (0.32 g, 4.8 mmol) and lithium 2-(difluoromethyl)-4-hydroxy-2-methylbutanoate (39e, 0.40 g, 2.4 mmol) in DMF (6.0 mL) at room temperature, TBSCl (0.43 g, 2.9 mmol) was added and the mixture was stirred at room temperature for 18 h. The material was purified by silica gel column chromatography (10% EtOAc / petroleum ether) to give 4-((tert-butyldimethylsilyl)oxy)-2-(difluoromethyl)-2-methylbutanoic acid (39f) as an oil, which was used directly in the next step.

[0224] Step F - Synthesis of Compound 39g and Compound 39h To a stirred mixture of 4-((tert-butyldimethylsilyl)oxy)-2-(difluoromethyl)-2-methylbutanoic acid (39f, 500 mg, 1.8 mmol) in DMF (2.0 mL) at room temperature, DIPEA (0.10 mL, 0.57 mmol) and HATU (86 mg, 0.23 mmol) were added and stirred for 5 min, followed by (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 100 mg, 0.19 mmol). The mixture was stirred at room temperature for 30 min. The material was purified by reverse phase column chromatography (75-100% MeCN / water (with 0.1% formic acid modifier)) to give 4-((tert-butyldimethylsilyl)oxy)-2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)bromo[1,2-b]quinolin-1-yl] The tanamide (39 g, peak 1) was obtained as a solid, and 4-((tert-butyldimethylsilyl)oxy)-2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)butanamide (39 h, peak 2) was obtained as a solid.

[0225] MS: m / z = 700 [M+H]. Step G - Synthesis of Compound 39 and Compound 40 To a stirred mixture of 4-((tert-butyldimethylsilyl)oxy)-2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-methylbutanamide (40 mg, 0.057 mmol, 39 g, peak 1) in DMF / MeOH (0.75 mL) at room temperature was added TFA (0.050 mL, 0.65 mmol) and the mixture was stirred at room temperature for 1 hour. Then, additional TFA (0.10 mL) was added and the mixture was stirred at room temperature for 0.5 hours. The residue was purified by reverse phase column chromatography (30-60% MeCN / water (with 0.1% formic acid modifier)) followed by repurification by reverse phase column chromatography (26-56% MeCN / water (with 0.1% formic acid modifier)) to give 2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methylbutanamide (40) as a solid.

[0226] MS: m / z = 586 [M+H]. 1H NMR (DMSO-d6, 400 MHz) δ 8.36 (br d, 1H, J = 8.1 Hz), 7.81 (d, 1H, J = 11.0 Hz), 7.32 (s, 1H), 6.52 (s, 1H), 6.1 - 6.5 (m, 1H), 5.6 - 5.7 (m, 1H), 5.42 (s, 2H), 5.2 - 5.3 (m, 1H), 5.05 (br d, 1H, J = 18.8 Hz), 4.65 (t, 1H, J = 4.8 Hz), 3.40 - 3.70 (m, 2H), 3.11 - 3.20 (m, 2H), 2.41 (s, 3H), 2.01 - 2.21 (m, 2H), 1.84 - 1.88 (m, 3H), 1.60 - 1.71 (m, 1H), 1.22 (s, 3H), 0.88 (br t, 3H, J = 7.3 Hz).

[0227] To a stirred mixture of 4-((tert-butyldimethylsilyl)oxy)-2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-methylbutanamide (39h, 45 mg, 0.064 mmol, peak 2) in DMF / MeOH (0.75 mL) at room temperature was added TFA (0.050 mL, 0.65 mmol) and the mixture was stirred at room temperature for 1 h. The residue was purified by reverse phase column chromatography (30-60% MeCN / water (with 0.1% formic acid modifier)) to give 2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methylbutanamide (39) as a solid.

[0228] MS: m / z = 586 [M+H]. 11H NMR (DMSO-d6, 400 MHz) δ 8.42 (d, 1H, J = 8.1 Hz), 7.86 (d, 1H, J = 11.0 Hz), 7.36 (s, 1H), 6.59 (s, 1H), 6.27 (br t, 1H, J = 56.3 Hz), 5.6 - 5.8 (m, 1H), 5.47 (s, 2H), 5.3 - 5.4 (m, 1H), 5.07 (d, 1H, J = 18.8 Hz), 4.70 (t, 1H, J = 4.9 Hz), 3.5 - 3.6 (m, 2H), 3.1 - 3.3 (m, 2H), 2.45 (s, 3H), 2.07 - 2.17 (m, 2H), 1.84 - 1.93 (m, 3H), 1.61 - 1.67 (m, 1H), 1.27 (s, 3H), 0.87 (t, 3H, J = 7.2 Hz).

[0229] Example 11 Preparation of compound 41

Chem.

[0230] MS: m / z = 621 [M+H]. Step B - Synthesis of Compound 41 A mixture of tert-butyl (1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2-methyl-1-oxopropan-2-yl)carbamate (41b, 58 mg, 0.094 mmol) with 4M HCl in dioxane (0.35 mL, 1.4 mmol) and dioxane (0.65 mL) was stirred at room temperature for 2.5 h and monitored by LCMS. The mixture was then diluted with HO and subjected to reverse phase column chromatography (10-70% MeCN / HO with 0.1% formic acid modifier) ​​to give 2-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-methylpropanamide formate (41) as a solid.

[0231] MS: m / z = 521 [M+H]. 1 H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.27 (s, 1H), 7.78 (d, J = 10.9 Hz, 1H), 7.30 (s, 1H), 5.53 (t, J = 5.2 Hz, 1H), 5.41 (s, 2H), 5.16 (s, 2H), 3.16 (t, J = 6.1 Hz, 2H), 2.39 (s, 3H), 2.22 - 2.08 (m, 2H), 1.93 - 1.78 (m, 2H), 1.37 (s, 3H), 1.33 (s, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[0232] The following compounds of the present disclosure in Table 7 were prepared using methods similar to those described in Example 11, varying reaction times (10-30 minutes for Step A, 3-7 hours for Step B) and substituting the appropriate reactants and / or reagents:

[0233] [Table 8]

[0234] Example 12 Preparation of compound 45 [ka] Step A - Synthesis of Compound 45 To a stirred mixture of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 270 μL, 0.095-0.11 mmol, ca. 0.35-0.40 M in DMF (containing 3 eq. EtN)), (((9H-fluoren-9-yl)methoxy)carbonyl)-L-serine (45a, 39 mg, 0.12 mmol), Hunig's base (18 μL, 0.10 mmol) and DMF (270 μL) was added HATU (46 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 5 min, at which point 4-methylpiperidine (59 μL, 0.50 mmol) was added. The mixture was stirred at room temperature for an additional 45 min and monitored by LCMS. The reaction mixture was then subjected to reverse phase column chromatography (10-60% MeCN / HO (with 0.1% formic acid modifier)) to afford (S)-2-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide formate (45) as a solid.

[0235] MS: m / z = 523 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.23 ​​(s, 1H), 7.79 (d, J = 10.9 Hz, 1H), 7.30 (s, 1H), 5.57 (apparent s, 1H), 5.42 (s, 2H), 5.27 - 5.14 (m, 2H), 3.63 - 3.44 (m, 3H), 3.24 - 3.08 (m, 2H), 2.39 (s, 3H), 2.26 - 2.18 (m, 1H), 2.17 - 2.05 (m, 1H), 1.97 - 1.76 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0236] The following compounds of the present disclosure in Table 8 were prepared using methods similar to those described in Example 12, varying reaction times (5 min to 2 h for the coupling step, 30 min to 14 h and up to 40° C. for the Fmoc deprotection step) and substituting the appropriate reactants and / or reagents:

[0237] [Table 9]

[0238] Example 13 Preparation of compound 49 [ka] Step A - Synthesis of Compound 49b To a mixture of 3,3-difluoropyrrolidin-2-one (49a, 1.6 g, 13 mmol), Boc-anhydride (6.1 mL, 26 mmol) and DMF (13 mL) was added DMAP (0.16 g, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with DCM, washed three times with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude tert-butyl 3,3-difluoro-2-oxopyrrolidine-1-carboxylate (49b) as an oil, which was used directly in the next reaction.

[0239] Step B - Synthesis of Compound 49c A mixture of crude tert-butyl 3,3-difluoro-2-oxopyrrolidine-1-carboxylate (49b, 181 mg, 0.82 mmol), lithium hydroxide (9.6 mg, 0.40 mmol) and DMF (0.40 mL) was stirred at 60° C. for 30 min and then at room temperature overnight. To the resulting suspension was added (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 540 μL, 0.19-0.22 mmol, ca. 0.35-0.40 M in DMF (containing 3.0 eq. EtN)) and HATU (140 mg, 0.36 mmol). The mixture was stirred at room temperature for 20 min. The mixture was then solubilized with DMSO (1.0 mL) and subjected to reverse phase column chromatography (10-100% MeCN / HO with 0.1% formic acid modifier) ​​to give tert-butyl (4-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-4-oxobutyl)carbamate (49c) as a solid.

[0240] Step C - Synthesis of Compound 49 A mixture of tert-butyl (4-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-4-oxobutyl)carbamate (49c, 30 mg, 0.045 mmol), TFA (35 μL, 0.45 mmol), and DCM (0.30 mL) was stirred at room temperature for 5 h. The mixture was then diluted with DMSO and subjected to reverse phase column chromatography (10-70% MeCN / HO with 0.1% formic acid modifier) ​​to give 4-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluorobutanamide (49) as a solid.

[0241] MS: m / z = 557 [M+H]. 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.81 (d, J = 10.9 Hz, 1H), 7.32 (s, 1H), 6.54 (br s, 1H), 5.60 (t, J = 5.5 Hz, 1H), 5.42 (s, 2H), 5.25 (d, J = 18.6 Hz, 1H), 5.10 (d, J = 18.6 Hz, 1H), 3.24 - 3.11 (m, 2H), 2.81 (t, J = 6.9 Hz, 2H), 2.40 (s, 3H), 2.38 - 2.26 (m, 2H), 2.25 - 2.13 (m, 2H), 1.96 - 1.79 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0242] Example 14 Preparation of compound 50 [ka] Step A - Synthesis of Compound 50b (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propanoic acid (50a, 51 mg, 0.12 mmol) and Hunig's base (21 μL, 0.12 mmol) with (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-aminium methanesulfonate (1a, 290 μL, 0.10-0.12 mmol, ca. 0.35-0.40 M (3.0 eq.) in DMF. To a stirred mixture of EtN (containing 1,2-dichlorophenyl) and DMF (0.30 mL) was added HATU (46 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 20 min, at which point 4-methylpiperidine (24 μL, 0.20 mmol) was added. After stirring at 40° C. for 2 h, the reaction mixture was subjected to reverse phase column chromatography (10-50% MeCN / HO with 0.1% formic acid modifier) ​​to give tert-butyl ((S)-2-amino-3-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3-oxopropyl)carbamate (50b) as a solid.

[0243] Step B - Synthesis of Compound 50 A mixture of tert-butyl ((S)-2-amino-3-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3-oxopropyl)carbamate (50b, 44 mg, 0.071 mmol), TFA (0.11 mL, 1.4 mmol), and DCM (0.30 mL) was stirred at room temperature for 45 min. The mixture was then quenched with N-methylmorpholine (0.16 mL, 1.4 mmol), diluted with water, and subjected to reverse phase column chromatography (10-50% MeCN / HO with 0.1% formic acid modifier) ​​to give (S)-2,3-diamino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)propanamide formate (50) as a solid.

[0244] MS: m / z = 522 [M+H]. 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (br s, 1H), 8.14 (s, 1H), 7.81 (d, J = 10.9 Hz, 1H), 7.32 (s, 1H), 6.67 (br s, 3H), 5.59 - 5.50 (m, 1H), 5.42 (s, 2H), 5.26 (d, J = 18.7 Hz, 1H), 5.20 (d, J = 18.8 Hz, 1H), 3.48 (dd, J = 8.9, 4.6 Hz, 1H), 3.23 - 3.16 (m, 2H), 3.08 (dd, J = 12.7, 4.6 Hz, 1H), 2.81 (dd, J = 12.7, 9.0 Hz, 1H), 2.41 (s, 3H), 2.27 - 2.18 (m, 1H), 2.18 - 2.07 (m, 1H), 1.93 - 1.78 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0245] Example 15 Preparation of compound 51 [ka] Step A - Synthesis of Compound 51 A mixture of (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-1-aminium methanesulfonate (1a, 270 μL, 0.095-0.11 mmol, ca. 0.35-0.40 M in DMF (containing 3 eq. TEA)), 2-iodoethanol (16 μL, 0.020 mmol), DIPEA (35 μL, 0.20 mmol), and DMF (0.20 mL) was stirred at 40 °C for 3 days. The mixture was then directly purified by reverse phase column chromatography (10-90% MeCN / water (with 0.1% formic acid modifier)) to give (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxyethyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione formate (51).

[0246] MS: m / z = 480 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.73 (d, J = 11.0 Hz, 1H), 7.30 (s, 1H), 6.51 (s, 1H), 5.45 - 5.31 (m, 4H), 4.33 (s, 1H), 3.58 - 3.48 (m, 2H), 3.24 - 3.13 (m, 1H), 3.02 (dt, J = 17.2, 5.0 Hz, 1H), 2.88 (dt, J = 11.6, 6.2 Hz, 1H), 2.77 (dt, J = 11.5, 5.6 Hz, 1H), 2.37 (s, 3H), 2.32 - 2.23 (m, 1H), 2.11 - 2.00 (m, 1H), 1.95 - 1.78 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0247] The following compounds of the present disclosure in Table 9 were prepared using methods similar to those described in Example 15, varying reaction times (from 2 hours to 1 week) and temperatures (23-50° C.) and substituting the appropriate alkyl electrophile:

[0248] [Table 10] TIFF2025511436000058.tif219122TIFF2025511436000059.tif158126

[0249] Example 16 Preparation of Compound 60 [ka] Step A - Synthesis of Compound 60 To a suspension of (1S,9S)-1-((2,2-difluoroethyl)amino)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione (I-60a, 17 mg, 0.035 mmol) in MeOH (0.70 mL) at 0 °C was added formaldehyde (37 wt% in water, 26 μL, 0.35 mmol), acetic acid (4.0 μL, 0.070 mmol) and sodium triacetoxyborohydride (15 mg, 0.070 mmol). After 6 hours, DCM (0.60 mL) was added to solubilize the mixture, followed by the addition of formaldehyde (37 wt% in water, 26 μL, 0.35 mmol), acetic acid (4.0 μL, 0.070 mmol), and sodium triacetoxyborohydride (15 mg, 0.070 mmol). The mixture was stirred at room temperature for 3 days. At this point, formaldehyde (37 wt% in water, 52 μL, 0.70 mmol), acetic acid (8.0 μL, 0.14 mmol), and sodium triacetoxyborohydride (29 mg, 0.14 mmol) were added and the mixture was stirred at room temperature for 30 minutes. This step was repeated once more. The mixture was then subjected to reverse phase column chromatography (30-90% MeCN / HO with 0.1% formic acid modifier) ​​to give (1S,9S)-1-((2,2-difluoroethyl)(methyl)amino)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione as a solid.

[0250] MS: m / z = 514 [M+H]. 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, J = 10.8 Hz, 1H), 7.31 (s, 1H), 6.49 (s, 1H), 6.29 (tt, J = 56.3, 4.1 Hz, 1H), 5.42 (s, 2H), 5.37 (d, J = 19.6 Hz, 1H), 5.27 (d, J = 19.8 Hz, 1H), 4.45 (dd, J = 10.9, 4.6 Hz, 1H), 3.07 - 2.85 (m, 2H), 2.37 (s, 3H), 2.34 - 2.22 (m, 4H), 2.11 - 1.99 (m, 1H), 1.94 - 1.79 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0251] Example 17 CellTiter-Glo® 2.0 Cytotoxicity Assay Step 1: Day 0, seed 384-well plates for assay (45uL per well) Jeko-1 cells were rapidly thawed by placing them in a cryovial and incubating them in a 37 °C water bath for less than 1 min until only a small amount of ice remained in the vial. The vial was quickly removed and wiped with 70% ethanol. The cells were transferred from the vial to a sterile centrifuge tube containing 8 mL of pre-warmed cell culture medium. An additional 1 mL of medium was flushed through the vial to completely transfer the cells to the centrifuge tube. The cells were then centrifuged at 150 × g for 5 min. The supernatant was aspirated and the cell pellet was resuspended in 10–20 mL of cell culture medium. The cells were counted using Vi-cell and found to be 6.6 × 10 4 Cells / mL, 3000 cells / 45uL per well was prepared. 45uL / well of cells were then added to Corning® 384-well Low Flange White Flat Bottom Polystyrene TC-treated Microplates (Corning, Cat#3570) using a Standard Cassette Combi (if necessary, dispense 1 dummy plate with 20uL to help standardize the Combi, use medium speed). Plates were spun down at 150×g for 30 seconds.

[0252] Phase 2: Day 1, Compound Addition Compound plates and reference compound stocks were removed and allowed to thaw at room temperature. The tubes were centrifuged at 2000×g for 30 seconds. 10× intermediate assay plates (Greiner plates, Cat#781280) were prepared using an Echo liquid handler. Serial dilutions were made using the appropriate buffer (HBSS (Gibco, Cat#14025-092)+10 mM HEPES (Gibco, Cat#15630-080)+0.1% BSA (Sigma, Cat#A9576)). For Max_E, media (without cells) was used. Compounds (5 uL of 10×) were transferred from intermediate plates to assay plates using a Bravo liquid handler at a very slow speed to avoid disturbing the cell monolayer. Plates were spun down at 150×g for 30 seconds.

[0253] Step 3: Day 4 or 5, CellTiter-Glo 2.0 Assay (Promega, Cat# G9242) (CellTiter-Glo kits are stored at -70°C) CellTiter-Glo® 2.0 Reagent was thawed overnight at 4°C (taking care not to expose the reagent to temperatures above 25°C). The kit was allowed to equilibrate to room temperature for approximately 30 minutes. CellTiter-Glo® 2.0 Reagent (20 μL) was added to 50 μL of medium containing cells using a Standard Cassette Combi. The contents were mixed on an orbital shaker for 2-3 minutes to induce cell lysis. The plate was spun down at 150×g for 30 seconds. The plate was incubated at room temperature for 5 minutes to stabilize the luminescence signal. Luminescence was recorded and EC was determined using an integration time of 0.25-1 second per well as a guideline. 50 values ​​were calculated.

[0254] Exemplary compounds of the disclosure were tested in the assay described above in Example 15. The results are provided in Table 9 below. [Table 11] TIFF2025511436000062.tif22270

Claims

1. Structural formula I 【Chemistry 1】 [During the ceremony, R ｋ is hydrogen, -C １－６ Alkyl, (CH ２ ) ｎ C(O)NHC １－６ Alkyl, (CH ２ ) ｎ C ６－１０ Aryl, and 【Chemistry 2】 wherein the alkyl and aryl are selected from hydroxyl, -C １－６ optionally substituted with 1 to 3 alkylOH groups, said alkyl being further optionally substituted with 1 to 10 halogen groups; R ｊ is hydrogen or C １－６ represents an alkyl group, wherein the alkyl group is optionally substituted with 1 to 10 halogens; R ２ and R ３ are independently hydrogen, -C １－６ Alkyl, OH, -C １－６ AlkylOH, halogen, -C １－９ Haloalkyl, -(CH ２ ) ｎ N.H. ２ , -NHC １－６ Alkyl, -N(C １－６ Alkyl) ２ , -C ３－６ Cycloalkyl, -(CH ２ ) ｎ C ６－１０ Aryl and -(CH ２ ) ｎ O.C. １－６ alkyl, where R ２ and R ３ are not both halogens at the same time; R ４ is C １－６ Alkyl, OH, -C １－６ AlkylOH, -CH(OH)C １－６ Alkyl, -C １－９ Haloalkyl, halogen, -C ３－６ Cycloalkyl, -(CH ２ ) ｎ O.C. １－３ Alkyl, -(CH ２ ) ｎ O.C. １－９ Haloalkyl, -CR ｘ R ｙ C １－６ AlkylOH, -(CH ２ ) ｎ N.H. ２ , -NHC １－６ Alkyl, -N(C １－６ Alkyl) ２ and -NHC(O)C １－６ Alkyl NH ２ Selected from: R ｘ and R ｙ is C １－３ Represents an alkylene, which, in combination, represents C ３－６ forms a cycloalkyl or spirocycloalkyl; Each n independently represents 0, 1, 2, or 3. or a pharma- ceutically acceptable salt or solvate thereof.

2. R ２ , R ３ and / or R ４ 2. The compound of claim 1, wherein any hydrogen atom in the alkyl of is not deuterated, or a pharma- ceutically acceptable salt or solvate thereof.

3. R ２ is hydrogen, C １－６ Alkyl, CH ２ O.C. １－６ Alkyl, -CH ２ OH, -O(CH ２ ) ２ OH, -CH ２ F, -CHF ２ , -CF ３ , -(CH ２ ) phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ２ ) ｎ N.H. ２ , -NHCH ３ and -N(CH ３ ) ２ 2. The compound of claim 1, selected from:

4. R ２ is hydrogen, C １－６ Alkyl, (CH ２ ) ｎ OCH ３ , —OH, —CH ２ OH, -CH ２ F, -CHF ２ , -CF ３ and -NH ２ or a pharma- ceutically acceptable salt or solvate thereof.

5. R ３ is hydrogen, C １－６ Alkyl, CH ２ O.C. １－６ Alkyl, -CH ２ OH, -(CH ２ ) ２ OH, -CH ２ F, -CHF ２ , -CF ３ , -(CH ２ ) phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ２ ) ｎ N.H. ２ , -NHCH ３ and -N(CH ３ ) ２ or a pharma- ceutically acceptable salt or solvate thereof.

6. R ３ is hydrogen, C １－６ Alkyl, (CH ２ ) ｎ OCH ３ , —OH, —CH ２ OH, -CH ２ F, -CHF ２ , -CF ３ and -NH ２ or a pharma- ceutically acceptable salt or solvate thereof.

7. R ２ and R ３ One of the groups is -OH -CH ２ OH, -(CH ２ ) ２ OH and (CH ２ ) ｎ N.H. ２ and the other is selected from hydrogen, CH ２ Phenyl and C １－６ 7. The compound of claim 1-6, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is selected from the group consisting of alkyl, aryl ... and aryl;

8. R ４ But, CH ３ , OH, -CH ２ OH, -(CH ２ ) ２ OH, -CH(CH ３ )OH, -CH ２ F, -CHF ２ , -CF ３ , (CH ２ ) ｎ O.C.F. ２ , cyclopropyl, -(CH ２ ) ｎ N.H. ２ and -cyclopropyl CH ２ OH, -NHC(O)CH(CH ３ ) N.H. ２ or a pharma- ceutically acceptable salt or solvate thereof.

9. R ４ OH, -(CH ２ ) ｎ OH, -CH(CH ３ )OH, -(CH ２ ) ｎ N.H. ２ Or R ４ But -CR ｘ R ｙ C １－６ alkylOH, where R ｘ and R ｙ are alkylene substituents which combine to form a cyclopropyl; or a pharma- ceutically acceptable salt or solvate thereof.

10. R ２ and R ３ One of the groups is —OH or —C １－６ alkylOH and the other is hydrogen, CH ２ Phenyl and C １－６ alkyl, and R ４ But, CH ３ , OH, -C １－６ AlkylOH, -C １－３ Haloalkyl, -CR ｘ R ｙ C １－６ AlkylOH, -(CH ２ ) ｎ N.H. ２ , -NHC １－６ Alkyl, -N(C １－６ Alkyl) ２ and -NHC(O)C １－６ Alkyl NH ２ 2. The compound of claim 1, selected from:

11. R ２ and R ３ One of the groups is —OH or —C １－６ alkylOH and the other is hydrogen, CH ２ Phenyl and C １－６ alkyl, and R ４ But -CH ２ OH, -(CH ２ ) ２ OH, -CH(CH ３ )OH, -CH ２ F, -CHF ２ , -CF ３ and -(CH ２ ) ｎ N.H. ２ 11. The compound of claim 10, selected from: or a pharma- ceutically acceptable salt or solvate thereof.

12. R ２ and R ３ One of the groups is -(CH ２ ) ｎ N.H. ２ , -NHCH ３ or -N(CH ３ ) ２ and the other is hydrogen, CH ２ Phenyl and C １－６ alkyl, and R ４ But, CH ３ , OH, -CH ２ OH, -(CH ２ ) ２ OH, -C １－３ Haloalkyl, -CR ｘ R ｙ C １－６ AlkylOH, -(CH ２ ) ｎ N.H. ２ , -NHC １－６ Alkyl, -N(C １－６ Alkyl) ２ and -NHC(O)C １－６ Alkyl NH ２ 2. The compound of claim 1, selected from:

13. R ２ and R ３ One of the two is (CH ２ ) ｎ N.H. ２ and the other is hydrogen, CH ２ Phenyl and C １－６ alkyl, and R ４ But -CH ２ OH, -(CH ２ ) ２ OH, -CH(CH ３ )OH, -CH ２ F, -CHF ２ , -CF ３ and -(CH ２ ) ｎ N.H. ２ 13. The compound of claim 12, selected from: or a pharma- ceutically acceptable salt or solvate thereof.

14. Structural formula II: 【Chemistry 3】 [In the formula, R ４ is -CH ２ OH, -(CH ２ ) ２ OH, -CH(CH ３ )OH, -CH ２ F, -CHF ２ , -CF ３ and -(CH ２ ) ｎ N.H. ２ selected from The compound according to any one of claims 1 to 13, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

15. Structural formula III: 【Chemistry 4】 [In the formula, R ４ is CH ３ , -CH ２ OH, -(CH ２ ) ２ OH, -CH(CH ３ )OH, -CH ２ F, -CHF ２ , -CF ３ and -(CH ２ ) ｎ N.H. ２ selected from The compound according to any one of claims 1 to 13, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

16. Structural formula IV: 【Chemistry 5】 [In the formula, R ４ is -CH ２ F, -CHF ２ , -CF ３ Or (CH ２ ) ｎ N.H. ２ is The compound according to any one of claims 1 to 13, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt or solvate thereof.

17. N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxybutanamide; (R)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxybutanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxybutanamide; (S)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxybutanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxy-3,3-dimethylbutanamide; (R)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxy-3,3-dimethylbutanamide; (S)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,4-dihydroxy-3,3-dimethylbutanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,3-dihydroxy-2-methylpropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,3-dihydroxy-2-methylpropanamide; N-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,3-dihydroxy-2-methylpropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,3-dihydroxy-2-methylpropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,3-dihydroxy-2-methylpropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluoro-3-hydroxybutanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluoro-3-hydroxybutanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluoro-3-hydroxybutanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluoro-3-hydroxybutanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluoro-3-hydroxypropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluoro-3-hydroxypropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-(hydroxymethyl)propenamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-(hydroxymethyl)propenamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-(hydroxymethyl)propenamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-(hydroxymethyl)propenamide; 1-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-2-methyl-1-oxopropan-2-aminium; 1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-2-methyl-1-oxopropan-2-aminium; 1-((-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-2-methyl-1-oxopropan-2-aminium; 1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-2-methyl-1-oxopropan-2-aminium; 3-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-1,1,1-trifluoro-3-oxopropan-2-aminium; 3-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-1,1,1-trifluoro-3-oxopropan-2-aminium; ((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-1,1,1-trifluoro-3-oxopropan-2-aminium; (((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-1,1,1-trifluoro-3-oxopropan-2-aminium; 2-amino-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-methylpropanamide; 2-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-methylpropanamide; 2-amino-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-methylpropanamide; 2-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoro-2-methylpropanamide; 2-amino-2-benzyl-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoropropanamide; 2-amino-2-benzyl-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoropropanamide; 2-amino-2-benzyl-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoropropanamide; 2-amino-2-benzyl-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3,3,3-trifluoropropanamide; 2-amino-2-cyclopropyl-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)propenamide; 2-amino-2-cyclopropyl-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)propenamide; 4-(difluoromethoxy)-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxybutanamide; (R)-4-(difluoromethoxy)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxybutanamide; 2-cyclopropyl-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; 2-cyclopropyl-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; 2-cyclopropyl-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; 2-cyclopropyl-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2,2-dimethylpropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2,2-dimethylpropanamide; (S)—N-(-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxybutanamide; (S)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxybutanamide; N-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxybutanamide; (R)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxybutanamide; N-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; 1-(2,3-dihydroxypropanamido)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-7-ium hexafluorophosphate (V); (1S,9S)-1-((S)-2,3-dihydroxypropanamido)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-7-ium hexafluorophosphate (V); 1-(2,3-dihydroxypropanamido)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-7-ium hexafluorophosphate (V); (1S,9S)-1-((R)-2,3-dihydroxypropanamido)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-7-ium hexafluorophosphate (V); N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxy-2-(1-(hydroxymethyl)cyclopropyl)acetamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-hydroxy-2-(1-(hydroxymethyl)cyclopropyl)acetamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methoxybutanamide; (R)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methoxybutanamide; (S)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methoxybutanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2-methylpropanamide; (S)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2-methylpropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2-methylpropanamide; (R)—N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxy-2-methylpropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxypropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxypropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxypropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxypropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxy-2-methylpropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxy-2-methylpropanamide; (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxypropyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxy-2-methylpropanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-fluoro-3-hydroxy-2-methylpropanamide; N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2,2-dimethylbutanamide; N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2,2-dimethylbutanamide; 2-(difluoromethyl)-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methylbutanamide; 2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methylbutanamide; 2-(difluoromethyl)-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methylbutanamide; 2-(difluoromethyl)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-4-hydroxy-2-methylbutanamide; 2-amino-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-methylpropanamide; 2-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2-methylpropanamide; 1-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-4-methyl-1-oxopentan-2-aminium; 1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-4-methyl-1-oxopentan-2-aminium; 3-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2-hydroxy-3-oxopropan-1-aminium; (R)-3-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2-hydroxy-3-oxopropan-1-aminium; 3-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2-hydroxy-3-oxopropan-1-aminium; (S)-3-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-2-hydroxy-3-oxopropan-1-aminium; 2-amino-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; (S)-2-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-3-hydroxypropanamide; 1-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3-hydroxy-1-oxopropan-2-aminium; (R)-1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3-hydroxy-1-oxopropan-2-aminium; 1-((1-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-2-methyl-1-oxopropan-2-yl)amino)-1-oxopropan-2-aminium; (2R)-1-((1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-2-methyl-1-oxopropan-2-yl)amino)-1-oxopropan-2-aminium; (2S)-1-((1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3,3-difluoro-2-methyl-1-oxopropan-2-yl)amino)-1-oxopropan-2-aminium; 1-((9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3-methoxy-2-methyl-1-oxopropan-2-aminium; 1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3-methoxy-2-methyl-1-oxopropan-2-aminium; 1-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-3-methoxy-2-methyl-1-oxopropan-2-aminium; 4-amino-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluorobutanamide; 4-amino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2,2-difluorobutanamide; 2,3-diamino-N-(9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)propanamide; (S)-2,3-diamino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)propanamide; (R)-2,3-diamino-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)propanamide; (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-hydroxyethyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((3-hydroxypropyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((1-hydroxypropan-2-yl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; (1S,9S)-1-((3,3-difluoro-2-hydroxypropyl)amino)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; 2-(((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)amino)-N-isopropylacetamide; (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-1-((2-(hydroxymethyl)benzyl)amino)-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; (1S,9S)-1-((2,2-difluoropropyl)amino)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; (1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1-((2,2,3,3-tetrafluoropropyl)amino)-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; (1S,9S)-1-((1,1-difluoropropan-2-yl)amino)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; or (1S,9S)-1-((2,2-difluoroethyl)(methyl)amino)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione; or a pharma- ceutically acceptable salt or solvate thereof.

18. below, 【Table 1】 18. The compound of claim 17, which is: or a pharma- ceutically acceptable salt or solvate thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier.

20. Use of a compound according to any one of claims 1 to 18 or a pharma- ceutically acceptable salt or solvate thereof, or use of a pharmaceutical composition according to claim 19, for the manufacture of a medicament for the treatment or prevention of cancer or tumors.

21. breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (e.g., acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer in subjects in need thereof; 20. A method for treating or preventing a cancer selected from skin cancer, thyroid cancer, pancreatic cancer, and lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, or recurrent anaplastic large cell lymphoma), comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising said compound, salt, or solvate.

22. A method for treating and / or preventing a tumor, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof.

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